{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:04:08Z","timestamp":1790435048278,"version":"4.1.0"},"reference-count":251,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,2]],"date-time":"2021-10-02T00:00:00Z","timestamp":1633132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["CZ.02.1.01\/0.0\/0.0\/16_019\/0000729"],"award-info":[{"award-number":["CZ.02.1.01\/0.0\/0.0\/16_019\/0000729"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Viral proteases are indispensable for successful virion maturation, thus making them a prominent drug target. Their enzyme activity is tightly spatiotemporally regulated by expression in the precursor form with little or no activity, followed by activation via autoprocessing. These cleavage events are frequently triggered upon transportation to a specific compartment inside the host cell. Typically, precursor oligomerization or the presence of a co-factor is needed for activation. A detailed understanding of these mechanisms will allow ligands with non-canonical mechanisms of action to be designed, which would specifically modulate the initial irreversible steps of viral protease autoactivation. Binding sites exclusive to the precursor, including binding sites beyond the protease domain, can be exploited. Both inhibition and up-regulation of the proteolytic activity of viral proteases can be detrimental for the virus. All these possibilities are discussed using examples of medically relevant viruses including herpesviruses, adenoviruses, retroviruses, picornaviruses, caliciviruses, togaviruses, flaviviruses, and coronaviruses.<\/jats:p>","DOI":"10.3390\/v13101981","type":"journal-article","created":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T01:59:47Z","timestamp":1633917587000},"page":"1981","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Precursors of Viral Proteases as Distinct Drug Targets"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5536-3587","authenticated-orcid":false,"given":"Ta\u0165\u00e1na","family":"Majerov\u00e1","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n\u00e1m. 2, 166 10 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Novotn\u00fd","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n\u00e1m. 2, 166 10 Prague, Czech Republic"},{"name":"Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University in Prague, 128 43 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1126\/science.180.4090.1022","article-title":"Zymogens of Proteolytic Enzymes","volume":"180","author":"Kassell","year":"1973","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/0006-3002(62)90612-1","article-title":"Partial structure of chymotrypsinogen","volume":"56","author":"Keil","year":"1962","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/0304-4165(66)90258-3","article-title":"Covalent structure of bovine chymotrypsinogen A","volume":"130","author":"Meloun","year":"1966","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1042\/bj1670855","article-title":"The first step in the activation of chicken pepsinogen is similar to that of prochymosin","volume":"167","author":"Keilova","year":"1977","journal-title":"Biochem. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/0305-0491(90)90183-T","article-title":"Molecular characteristics of pepsinogen and pepsin from duck glandular stomach","volume":"97","author":"Kostka","year":"1990","journal-title":"Comp. Biochem. Physiol. B"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0021-9673(01)88006-7","article-title":"Model study of hydrophobic interactions of alpha- and beta-trypsin and alpha-chymotrypsin","volume":"259","author":"Strop","year":"1983","journal-title":"J. Chromatogr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0378-4347(96)00293-9","article-title":"Fast detection of phosphorylation of human pepsinogen A, human pepsinogen C and swine pepsinogen using a combination of reversed-phase high-performance liquid chromatography and capillary zone electrophoresis for peptide mapping","volume":"688","author":"Hynek","year":"1997","journal-title":"J. Chromatogr. B Biomed. Sci. Appl."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"83","DOI":"10.2174\/1570163811209020083","article-title":"Discovery of anticoagulant drugs: A historical perspective","volume":"9","author":"Lecumberri","year":"2012","journal-title":"Curr. Drug Discov. Technol."},{"key":"ref_9","first-page":"143","article-title":"A review on prorennin and rennin","volume":"35","author":"Foltmann","year":"1966","journal-title":"C. R. Trav. Lab. Carlsberg"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/j.1432-1033.1982.tb06685.x","article-title":"Lysosomal enzyme precursors in human fibroblasts. Activation of cathepsin D precursor in vitro and activity of beta-hexosaminidase A precursor towards ganglioside GM2","volume":"125","author":"Hasilik","year":"1982","journal-title":"Eur. J. Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"15474","DOI":"10.1021\/bi0614986","article-title":"Cathepsin D propeptide: Mechanism and regulation of its interaction with the catalytic core","volume":"45","author":"Horn","year":"2006","journal-title":"Biochemistry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.chembiol.2018.01.001","article-title":"Novel Structural Mechanism of Allosteric Regulation of Aspartic Peptidases via an Evolutionarily Conserved Exosite","volume":"25","author":"Brynda","year":"2018","journal-title":"Cell Chem. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1021\/acs.jmedchem.9b01351","article-title":"Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure-Activity Relationship and Binding Mode Analysis","volume":"63","author":"Hadzima","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1126\/science.274.5285.255","article-title":"Cholesterol Modification of Hedgehog Signaling Proteins in Animal Development","volume":"274","author":"Porter","year":"1996","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"15615","DOI":"10.1074\/jbc.274.22.15615","article-title":"A Pathway for Conformational Diversity in Proteins Mediated by Intramolecular Chaperones","volume":"274","author":"Shinde","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Oh, H.S., Banerjee, S., Aponte-Diaz, D., Sharma, S.D., Aligo, J., Lodeiro, M.F., Ning, G., Sharma, R., Arnold, J.J., and Cameron, C.E. (2018). Multiple poliovirus-induced organelles suggested by comparison of spatiotemporal dynamics of membranous structures and phosphoinositides. PLoS Pathg., 14.","DOI":"10.1371\/journal.ppat.1007036"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.virol.2015.03.021","article-title":"Retroviral proteases and their roles in virion maturation","volume":"479\u2013480","author":"Konvalinka","year":"2015","journal-title":"Virology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1038\/s41467-021-21505-9","article-title":"Flavivirus maturation leads to the formation of an occupied lipid pocket in the surface glycoproteins","volume":"12","author":"Renner","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.virol.2014.04.027","article-title":"Membrane rearrangements mediated by coronavirus nonstructural proteins 3 and 4","volume":"458\u2013459","author":"Hagemeijer","year":"2014","journal-title":"Virology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","article-title":"Structure of M(pro) from SARS-CoV-2 and discovery of its inhibitors","volume":"582","author":"Jin","year":"2020","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"39470","DOI":"10.1074\/jbc.M112.388678","article-title":"Activity, Specificity, and Probe Design for the Smallpox Virus Protease K7L","volume":"287","author":"Aleshin","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/383275a0","article-title":"Unique fold and active site in cytomegalovirus protease","volume":"383","author":"Qiu","year":"1996","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"8295","DOI":"10.1002\/jcp.27715","article-title":"Expression of novel proteins by polyomaviruses and recent advances in the structural and functional features of agnoprotein of JC virus, BK virus, and simian virus 40","volume":"234","author":"Saribas","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1002\/jmv.25388","article-title":"Prevalence of antibodies against BKPyV subtype I and IV in kidney transplant recipients and in the general Czech population","volume":"91","year":"2019","journal-title":"J. Med. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1135\/cccc2009087","article-title":"Therapeutic targets for influenza-Perspectives in drug development","volume":"75","author":"Hoffman","year":"2010","journal-title":"Collect. Czechoslov. Chem. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yip, W.K.W., Cristi, F., Trifonov, G., Narayan, N., Kubanski, M., and Shmulevitz, M. (2021). The reovirus \u03bc2 C-terminal loop inversely regulates NTPase and transcription functions versus binding to factory-forming \u03bcNS and promotes replication in tumorigenic cells. J. Virol., 95.","DOI":"10.1128\/JVI.02006-20"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.ejmech.2019.01.025","article-title":"Hepatitis C\u2014New drugs and treatment prospects","volume":"165","author":"Muszalska","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11382","DOI":"10.1021\/cr500255e","article-title":"Current and Potential Treatments for Ubiquitous but Neglected Herpesvirus Infections","volume":"114","author":"Gable","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0166-3542(87)80004-9","article-title":"Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines","volume":"8","author":"Clercq","year":"1987","journal-title":"Antivir. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1128\/AAC.32.12.1839","article-title":"(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, a potent and selective inhibitor of human cytomegalovirus replication","volume":"32","author":"Snoeck","year":"1988","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/S0092-8674(00)80157-9","article-title":"Structure of the Human Cytomegalovirus Protease Catalytic Domain Reveals a Novel Serine Protease Fold and Catalytic Triad","volume":"86","author":"Chen","year":"1996","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7445","DOI":"10.1074\/jbc.271.13.7445","article-title":"Active human cytomegalovirus protease is a dimer","volume":"271","author":"Darke","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/383272a0","article-title":"A new serine-protease fold revealed by the crystal structure of human cytomegalovirus protease","volume":"383","author":"Tong","year":"1996","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/383279a0","article-title":"Three-dimensional structure of human cytomegalovirus protease","volume":"383","author":"Shieh","year":"1996","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5149","DOI":"10.1128\/jvi.65.10.5149-5156.1991","article-title":"The herpes simplex virus 1 gene encoding a protease also contains within its coding domain the gene encoding the more abundant substrate","volume":"65","author":"Liu","year":"1991","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1128\/jvi.71.2.1281-1291.1997","article-title":"Assembly of herpes simplex virus capsids using the human cytomegalovirus scaffold protein: Critical role of the C terminus","volume":"71","author":"Oien","year":"1997","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6838","DOI":"10.1128\/JVI.74.15.6838-6848.2000","article-title":"Evidence for controlled incorporation of herpes simplex virus type 1 UL26 protease into capsids","volume":"74","author":"Sheaffer","year":"2000","journal-title":"J. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1128\/jvi.67.1.497-506.1993","article-title":"Expression and analysis of the human cytomegalovirus UL80-encoded protease: Identification of autoproteolytic sites","volume":"67","author":"Baum","year":"1993","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"25911","DOI":"10.1016\/S0021-9258(18)47332-2","article-title":"Activity of two-chain recombinant human cytomegalovirus protease","volume":"269","author":"Holwerda","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"12961","DOI":"10.1128\/JVI.79.20.12961-12968.2005","article-title":"Cleavage of human cytomegalovirus protease pUL80a at internal and cryptic sites is not essential but enhances infectivity","volume":"79","author":"Loveland","year":"2005","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6657","DOI":"10.1128\/JVI.78.12.6657-6665.2004","article-title":"Herpesvirus protease inhibition by dimer disruption","volume":"78","author":"Shimba","year":"2004","journal-title":"J. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.jmb.2011.06.032","article-title":"Enzyme Inhibition by Allosteric Capture of an Inactive Conformation","volume":"411","author":"Lee","year":"2011","journal-title":"J. Mol. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1038\/nchembio.192","article-title":"Inhibition of a viral enzyme by a small-molecule dimer disruptor","volume":"5","author":"Shahian","year":"2009","journal-title":"Nat. Chem. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"30168","DOI":"10.1074\/jbc.270.50.30168","article-title":"Stimulation of the Herpes Simplex Virus Type I Protease by Antichaeotrophic Salts","volume":"270","author":"Yamanaka","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.molcel.2005.07.003","article-title":"A deubiquitinating enzyme encoded by HSV-1 belongs to a family of cysteine proteases that is conserved across the family Herpesviridae","volume":"19","author":"Kattenhorn","year":"2005","journal-title":"Mol. Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6003","DOI":"10.1128\/JVI.00401-06","article-title":"High-molecular-weight protein (pUL48) of human cytomegalovirus is a competent deubiquitinating protease: Mutant viruses altered in its active-site cysteine or histidine are viable","volume":"80","author":"Wang","year":"2006","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"15582","DOI":"10.1128\/JVI.79.24.15582-15585.2005","article-title":"A deubiquitinating activity is conserved in the large tegument protein of the herpesviridae","volume":"79","author":"Schlieker","year":"2005","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"12046","DOI":"10.1128\/JVI.00411-09","article-title":"Cleavage specificity of the UL48 deubiquitinating protease activity of human cytomegalovirus and the growth of an active-site mutant virus in cultured cells","volume":"83","author":"Kim","year":"2009","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"11851","DOI":"10.1128\/JVI.01211-13","article-title":"Herpes simplex virus 1 ubiquitin-specific protease UL36 inhibits beta interferon production by deubiquitinating TRAF3","volume":"87","author":"Wang","year":"2013","journal-title":"J. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Ye, R., Su, C., Xu, H., and Zheng, C. (2017). Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Abrogates NF-\u03baB Activation in DNA Sensing Signal Pathway. J. Virol., 91.","DOI":"10.1128\/JVI.02417-16"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Westergren Jakobsson, A., Segerman, B., Wallerman, O., Bergstr\u00f6m Lind, S., Zhao, H., Rubin, C.-J., Pettersson, U., and Akusj\u00e4rvi, G. (2021). The Human Adenovirus 2 Transcriptome: An Amazing Complexity of Alternatively Spliced mRNAs. J. Virol., 95.","DOI":"10.1128\/JVI.01869-20"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/0092-8674(80)90362-1","article-title":"DNA replication and the early to late transition in adenovirus infection","volume":"22","author":"Thomas","year":"1980","journal-title":"Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/s42003-020-0849-9","article-title":"Deep splicing plasticity of the human adenovirus type 5 transcriptome drives virus evolution","volume":"3","author":"Turnell","year":"2020","journal-title":"Commun. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3419","DOI":"10.1002\/1873-3468.13690","article-title":"Imaging the adenovirus infection cycle","volume":"593","author":"Pied","year":"2019","journal-title":"FEBS Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/0092-8674(93)90053-S","article-title":"The adenovirus protease is activated by a virus-coded disulphide-linked peptide","volume":"72","author":"Webster","year":"1993","journal-title":"Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/361274a0","article-title":"Viral DNA and a viral peptide can act as cofactors of adenovirus virion proteinase activity","volume":"361","author":"Mangel","year":"1993","journal-title":"Nature"},{"key":"ref_57","first-page":"2081","article-title":"Regulation of a Viral Proteinase by a Peptide and DNA in One-dimensional Space: III","volume":"288","author":"Baniecki","year":"2013","journal-title":"Atomic resolution structure of the nascent form of the adenoirus proteinase. J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"46298","DOI":"10.1074\/jbc.M202988200","article-title":"Actin can act as a cofactor for a viral proteinase in the cleavage of the cytoskeleton","volume":"277","author":"Brown","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1006\/viro.2000.0253","article-title":"The Effect of Mutant Peptide Cofactors on Adenovirus Protease Activity and Virus Infection","volume":"270","author":"Sircar","year":"2000","journal-title":"Virology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1126\/science.6189183","article-title":"Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS)","volume":"220","author":"Chermann","year":"1983","journal-title":"Science"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"7415","DOI":"10.1073\/pnas.77.12.7415","article-title":"Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma","volume":"77","author":"Poiesz","year":"1980","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1126\/science.6200936","article-title":"Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS","volume":"224","author":"Gallo","year":"1984","journal-title":"Science"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1128\/MMBR.00033-07","article-title":"Human RNA Viruses: The Search for Novel Human Retroviruses in Chronic Disease","volume":"72","author":"Voisset","year":"2008","journal-title":"Microbiol Mol. Biol. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0006-2952(94)90001-9","article-title":"HIV resistance to reverse transcriptase inhibitors","volume":"47","year":"1994","journal-title":"Biochem. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2801","DOI":"10.1135\/cccc19872801","article-title":"Synthesis of 9-(2-phosphonylmethoxyethyl)adenine and related compounds","volume":"52","author":"Rosenberg","year":"1987","journal-title":"Collect. Czechoslov. Chem. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1128\/AAC.37.2.332","article-title":"Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: Potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine","volume":"37","author":"Balzarini","year":"1993","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1126\/science.2183354","article-title":"Rational design of peptide-based HIV proteinase inhibitors","volume":"248","author":"Roberts","year":"1990","journal-title":"Science"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.3390\/v1031209","article-title":"Current and Novel Inhibitors of HIV Protease","volume":"1","author":"Machala","year":"2009","journal-title":"Viruses"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1146\/annurev.biophys.27.1.249","article-title":"Inhibitors of HIV-1 protease: A major success of structure-assisted drug design","volume":"27","author":"Wlodawer","year":"1998","journal-title":"Annu. Rev. Biophys. Biomol. Struct."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.ijbiomac.2021.01.076","article-title":"Trends and strategies to combat viral infections: A review on FDA approved antiviral drugs","volume":"172","author":"Tompa","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"5901","DOI":"10.1021\/jm400645w","article-title":"Carbamoyl pyridone HIV-1 integrase inhibitors 3. A diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir (S\/GSK1349572) and (S\/GSK1265744)","volume":"56","author":"Johns","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1021\/acs.biochem.1c00157","article-title":"Long-Acting Cabotegravir for HIV\/AIDS Prophylaxis","volume":"60","author":"Engelman","year":"2021","journal-title":"Biochemistry"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1080\/14756360802051578","article-title":"The strand transfer oligonucleotide inhibitors of HIV-integrase","volume":"24","author":"Rosenberg","year":"2009","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Hikichi, Y., Van Duyne, R., Pham, P., Groebner, J.L., Wiegand, A., Mellors, J.W., Kearney, M.F., and Freed, E.O. (2021). Mechanistic Analysis of the Broad Antiretroviral Resistance Conferred by HIV-1 Envelope Glycoprotein Mutations. mBio, 12.","DOI":"10.1128\/mBio.03134-20"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"4908","DOI":"10.1002\/jmv.26988","article-title":"HIV-1 subtypes and drug resistance in children during antiretroviral therapy in Brazil","volume":"93","author":"Lima","year":"2021","journal-title":"J. Med. Virol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3271","DOI":"10.1021\/acs.chemrev.0c00967","article-title":"Avoiding Drug Resistance in HIV Reverse Transcriptase","volume":"121","author":"Cilento","year":"2021","journal-title":"Chem. Rev."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Nka, A.D., Teto, G., Santoro, M.M., Ngum Ndze, V., Takou, D., Dambaya, B., Ngoufack Jagni Semengue, E., Fabeni, L., Perno, C.F., and Colizzi, V. (2021). HIV-1 Gag gene mutations, treatment response and drug resistance to protease inhibitors: A systematic review and meta-analysis protocol. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0253587"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.bbrc.2021.05.094","article-title":"Novel HIV PR inhibitors with C4-substituted bis-THF and bis-fluoro-benzyl target the two active site mutations of highly drug resistant mutant PR(S17)","volume":"566","author":"Agniswamy","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Weber, I.T., Wang, Y.F., and Harrison, R.W. (2021). HIV Protease: Historical Perspective and Current Research. Viruses, 13.","DOI":"10.3390\/v13050839"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4320","DOI":"10.1128\/AAC.00465-12","article-title":"Mutations in HIV-1 gag and pol compensate for the loss of viral fitness caused by a highly mutated protease","volume":"56","author":"Henke","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/1742-4690-8-70","article-title":"HIV-1 protease inhibitor mutations affect the development of HIV-1 resistance to the maturation inhibitor bevirimat","volume":"8","author":"Fun","year":"2011","journal-title":"Retrovirology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"8810","DOI":"10.1128\/JVI.00451-09","article-title":"Molecular characterization of clinical isolates of human immunodeficiency virus resistant to the protease inhibitor darunavir","volume":"83","author":"Brynda","year":"2009","journal-title":"J. Virol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1097\/QAI.0000000000002562","article-title":"Simulating HIV Breakthrough and Resistance Development During Variable Adherence to Antiretroviral Treatment","volume":"86","author":"Mulato","year":"2021","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1111\/hiv.12956","article-title":"Transmitted drug resistance to NRTIs and risk of virological failure in na\u00efve patients treated with integrase inhibitors","volume":"22","author":"Borghetti","year":"2021","journal-title":"HIV Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"110524","DOI":"10.1016\/j.jtbi.2020.110524","article-title":"Competition delays multi-drug resistance evolution during combination therapy","volume":"509","author":"Gifford","year":"2021","journal-title":"J. Theor. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1007\/s13181-013-0325-8","article-title":"A review of the toxicity of HIV medications","volume":"10","author":"Margolis","year":"2014","journal-title":"J. Med. Toxicol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"12234","DOI":"10.1073\/pnas.1400027111","article-title":"Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir","volume":"111","author":"Hayashi","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"13384","DOI":"10.1128\/JVI.07234-11","article-title":"Loss of the protease dimerization inhibition activity of tipranavir (TPV) and its association with the acquisition of resistance to TPV by HIV-1","volume":"86","author":"Aoki","year":"2012","journal-title":"J. Virol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"9072","DOI":"10.1073\/pnas.1102278108","article-title":"Inhibition of autoprocessing of natural variants and multidrug resistant mutant precursors of HIV-1 protease by clinical inhibitors","volume":"108","author":"Louis","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3620","DOI":"10.1128\/AAC.00055-12","article-title":"Activity of human immunodeficiency virus type 1 protease inhibitors against the initial autocleavage in Gag-Pol polyprotein processing","volume":"56","author":"Davis","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2390","DOI":"10.1021\/acs.biochem.6b00012","article-title":"Binding of Clinical Inhibitors to a Model Precursor of a Rationally Selected Multidrug Resistant HIV-1 Protease Is Significantly Weaker Than That to the Released Mature Enzyme","volume":"55","author":"Park","year":"2016","journal-title":"Biochemistry"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"10438","DOI":"10.1038\/s41598-018-28638-w","article-title":"Inhibition of the precursor and mature forms of HIV-1 protease as a tool for drug evaluation","volume":"8","author":"Weber","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrneph.2009.201","article-title":"Direct renin inhibition and the kidney","volume":"6","author":"Hollenberg","year":"2010","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.jmgm.2015.09.006","article-title":"Conformational variation of an extreme drug resistant mutant of HIV protease","volume":"62","author":"Shen","year":"2015","journal-title":"J. Mol. Graph. Model."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1021\/cb4008875","article-title":"Structures of Darunavir-Resistant HIV-1 Protease Mutant Reveal Atypical Binding of Darunavir to Wide Open Flaps","volume":"9","author":"Zhang","year":"2014","journal-title":"ACS Chem. Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/s41598-018-36730-4","article-title":"Targeting HIV-1 Protease Autoprocessing for High-throughput Drug Discovery and Drug Resistance Assessment","volume":"9","author":"Huang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Aoki, M., Das, D., Hayashi, H., Aoki-Ogata, H., Takamatsu, Y., Ghosh, A.K., Mitsuya, H., Prasad, V.R., Shafer, R., and Kovari, L. (2018). Mechanism of Darunavir (DRV)\u2019s High Genetic Barrier to HIV-1 Resistance: A Key V32I Substitution in Protease Rarely Occurs, but Once It Occurs, It Predisposes HIV-1 To Develop DRV Resistance. mBio, 9.","DOI":"10.1128\/mBio.02425-17"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"107826","DOI":"10.1016\/j.jmgm.2020.107826","article-title":"Understanding the mechanism of HIV-1 protease inhibition by monoclonal antibodies","volume":"103","author":"Gupta","year":"2021","journal-title":"J. Mol. Graph. Model."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.chembiol.2005.02.004","article-title":"Switching between allosteric and dimerization inhibition of HIV-1 protease","volume":"12","author":"Bowman","year":"2005","journal-title":"Chem. Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"18555","DOI":"10.1038\/srep18555","article-title":"HIV-1 Protease Dimerization Dynamics Reveals a Transient Druggable Binding Pocket at the Interface","volume":"5","author":"Pietrucci","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"28709","DOI":"10.1074\/jbc.M703938200","article-title":"Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization","volume":"282","author":"Koh","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"15591","DOI":"10.1016\/S0021-9258(18)98445-0","article-title":"Dissociative inhibition of dimeric enzymes. Kinetic characterization of the inhibition of HIV-1 protease by its COOH-terminal tetrapeptide","volume":"266","author":"Zhang","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1006\/bbrc.1996.0694","article-title":"A modular approach to HIV-1 proteinase inhibitor design","volume":"222","author":"Konvalinka","year":"1996","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1110\/ps.9.9.1631","article-title":"Systematic mutational analysis of the active-site threonine of HIV-1 proteinase: Rethinking the \u201cfireman\u2019s grip\u201d hypothesis","volume":"9","author":"Strisovsky","year":"2000","journal-title":"Protein Sci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1110\/ps.03171903","article-title":"Kinetics of the dimerization of retroviral proteases: The \u201cfireman\u2019s grip\u201d and dimerization","volume":"12","author":"Ingr","year":"2003","journal-title":"Protein Sci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1128\/JVI.75.4.1834-1841.2001","article-title":"Maintenance of the Gag\/Gag-Pol ratio is important for human immunodeficiency virus type 1 RNA dimerization and viral infectivity","volume":"75","author":"Crowe","year":"2001","journal-title":"J. Virol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"8477","DOI":"10.1128\/JVI.78.16.8477-8485.2004","article-title":"Initial cleavage of the human immunodeficiency virus type 1 GagPol precursor by its activated protease occurs by an intramolecular mechanism","volume":"78","author":"Pettit","year":"2004","journal-title":"J. Virol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"10601","DOI":"10.1128\/JVI.79.16.10601-10607.2005","article-title":"Ordered processing of the human immunodeficiency virus type 1 GagPol precursor is influenced by the context of the embedded viral protease","volume":"79","author":"Pettit","year":"2005","journal-title":"J. Virol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1128\/JVI.77.1.366-374.2003","article-title":"The dimer interfaces of protease and extra-protease domains influence the activation of protease and the specificity of GagPol cleavage","volume":"77","author":"Pettit","year":"2003","journal-title":"J. Virol."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Tien, C., Huang, L., Watanabe, S.M., Speidel, J.T., Carter, C.A., and Chen, C. (2018). Context-dependent autoprocessing of human immunodeficiency virus type 1 protease precursors. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191372"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1006\/viro.1998.9173","article-title":"Three active forms of aspartic proteinase from Mason-Pfizer monkey virus","volume":"245","author":"Hunter","year":"1998","journal-title":"Virology"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.jmb.2003.08.049","article-title":"Three-dimensional structure of a monomeric form of a retroviral protease","volume":"333","author":"Veverka","year":"2003","journal-title":"J. Mol. Biol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/nsmb.2119","article-title":"Crystal structure of a monomeric retroviral protease solved by protein folding game players","volume":"18","author":"Khatib","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1002\/pro.4072","article-title":"Crystal structures of inhibitor complexes of M-PMV protease with visible flap loops","volume":"30","author":"Wosicki","year":"2021","journal-title":"Protein Sci."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"15053","DOI":"10.1074\/jbc.270.25.15053","article-title":"Cloning, Bacterial Expression, and Characterization of the Mason-Pfizer Monkey Virus Proteinase","volume":"270","author":"Andreansky","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Nijhuis, M., van Maarseveen, N.M., Lastere, S., Schipper, P., Coakley, E., Glass, B., Rovenska, M., de Jong, D., Chappey, C., and Goedegebuure, I.W. (2007). A novel substrate-based HIV-1 protease inhibitor drug resistance mechanism. PLoS Med., 4.","DOI":"10.1371\/journal.pmed.0040036"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1007\/s00018-011-0859-3","article-title":"Protein intrinsic disorder as a flexible armor and a weapon of HIV-1","volume":"69","author":"Xue","year":"2012","journal-title":"Cell Mol. Life Sci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/1742-4690-7-89","article-title":"Selective killing of human immunodeficiency virus infected cells by non-nucleoside reverse transcriptase inhibitor-induced activation of HIV protease","volume":"7","author":"Jochmans","year":"2010","journal-title":"Retrovirology"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"3348","DOI":"10.1128\/JVI.02306-12","article-title":"Efavirenz enhances HIV-1 gag processing at the plasma membrane through Gag-Pol dimerization","volume":"87","author":"Sudo","year":"2013","journal-title":"J. Virol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/1742-4690-11-37","article-title":"HIV-1 protease-induced apoptosis","volume":"11","author":"Ruml","year":"2014","journal-title":"Retrovirology"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1093\/jac\/dkr433","article-title":"A non-infectious cell-based phenotypic assay for the assessment of HIV-1 susceptibility to protease inhibitors","volume":"67","author":"Buzon","year":"2012","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2616","DOI":"10.1128\/AAC.45.9.2616-2622.2001","article-title":"Cell-based fluorescence assay for human immunodeficiency virus type 1 protease activity","volume":"45","author":"Lindsten","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jcv.2006.01.014","article-title":"Non-infectious fluorimetric assay for phenotyping of drug-resistant HIV proteinase mutants","volume":"36","author":"Dantuma","year":"2006","journal-title":"J. Clin. Virol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"4528","DOI":"10.1073\/pnas.88.10.4528","article-title":"Human immunodeficiency virus type 1 Gag proteins are processed in two cellular compartments","volume":"88","author":"Kaplan","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s12977-019-0479-9","article-title":"NNRTI-induced HIV-1 protease-mediated cytotoxicity induces rapid death of CD4 T cells during productive infection and latency reversal","volume":"16","author":"Zhang","year":"2019","journal-title":"Retrovirology"},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Jurado, K.A., and Engelman, A. (2013). Multimodal mechanism of action of allosteric HIV-1 integrase inhibitors. Expert Rev. Mol. Med., 15.","DOI":"10.1017\/erm.2013.15"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"3213","DOI":"10.1073\/pnas.88.8.3213","article-title":"Human immunodeficiency virus proteinase dimer as component of the viral polyprotein prevents particle assembly and viral infectivity","volume":"88","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Pan, Y.Y., Wang, S.M., Huang, K.J., Chiang, C.C., and Wang, C.T. (2012). Placement of leucine zipper motifs at the carboxyl terminus of HIV-1 protease significantly reduces virion production. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032845"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1099\/vir.0.81601-0","article-title":"Effects of human immunodeficiency virus type 1 transframe protein p6* mutations on viral protease-mediated Gag processing","volume":"87","author":"Chiu","year":"2006","journal-title":"J. Gen. Virol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.virol.2008.10.038","article-title":"Premature processing of mouse mammary tumor virus Gag polyprotein impairs intracellular capsid assembly","volume":"384","author":"Sakalian","year":"2009","journal-title":"Virology"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/nature13838","article-title":"Structure of the immature HIV-1 capsid in intact virus particles at 8.8 \u00c5 resolution","volume":"517","author":"Schur","year":"2015","journal-title":"Nature"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1128\/JVI.02022-09","article-title":"Effect of dimerizing domains and basic residues on in vitro and in vivo assembly of Mason-Pfizer monkey virus and human immunodeficiency virus","volume":"84","author":"Tuma","year":"2010","journal-title":"J. Virol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"8819","DOI":"10.1074\/jbc.RA119.011991","article-title":"Differences and commonalities in plasma membrane recruitment of the two morphogenetically distinct retroviruses HIV-1 and MMTV","volume":"295","author":"Pleskot","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12977-017-0368-z","article-title":"Cellular fatty acid synthase is required for late stages of HIV-1 replication","volume":"14","author":"Kulkarni","year":"2017","journal-title":"Retrovirology"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"13037","DOI":"10.1073\/pnas.212409999","article-title":"Myristoylation as a target for inhibiting HIV assembly: Unsaturated fatty acids block viral budding","volume":"99","author":"Lindwasser","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s00705-017-3614-8","article-title":"Picornaviridae-the ever-growing virus family","volume":"163","author":"Zell","year":"2018","journal-title":"Arch. Virol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1021\/bi027004w","article-title":"The unusual catalytic triad of poliovirus protease 3C","volume":"42","year":"2003","journal-title":"Biochemistry"},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Horova, V., Lyoo, H., R\u00f3\u017cycki, B., Chalupska, D., Smola, M., Humpolickova, J., Strating, J.R.P.M., van Kuppeveld, F.J.M., Boura, E., and Klima, M. (2019). Convergent evolution in the mechanisms of ACBD3 recruitment to picornavirus replication sites. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1007962"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"12867","DOI":"10.1074\/jbc.274.18.12867","article-title":"Modulation of the RNA binding and protein processing activities of poliovirus polypeptide 3CD by the viral RNA polymerase domain","volume":"274","author":"Parsley","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"3583","DOI":"10.1128\/JVI.02306-06","article-title":"Crystal structure of poliovirus 3CD protein: Virally encoded protease and precursor to the RNA-dependent RNA polymerase","volume":"81","author":"Marcotte","year":"2007","journal-title":"J. Virol."},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Winston, D.S., and Boehr, D.D. (2021). The Picornavirus Precursor 3CD Has Different Conformational Dynamics Compared to 3C(pro) and 3D(pol) in Functionally Relevant Regions. Viruses, 13.","DOI":"10.3390\/v13030442"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.virol.2015.07.018","article-title":"Viral precursor protein P3 and its processed products perform discrete and essential functions in the poliovirus RNA replication complex","volume":"485","author":"Spear","year":"2015","journal-title":"Virology"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.str.2016.02.019","article-title":"Long-Range Communication between Different Functional Sites in the Picornaviral 3C Protein","volume":"24","author":"Chan","year":"2016","journal-title":"Structure"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"13499","DOI":"10.1073\/pnas.1918844117","article-title":"Inhibitory antibodies identify unique sites of therapeutic vulnerability in rhinovirus and other enteroviruses","volume":"117","author":"Meng","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1161\/CIRCULATIONAHA.114.009847","article-title":"Ubiquitin-like protein ISG15 (interferon-stimulated gene of 15 kDa) in host defense against heart failure in a mouse model of virus-induced cardiomyopathy","volume":"130","author":"Rahnefeld","year":"2014","journal-title":"Circulation"},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"von der Helm, K., Korant, B.D., and Cheronis, J.C. (2000). The 3C proteinases of picornaviruses. Proteases as Targets for Therapy, Springer.","DOI":"10.1007\/978-3-642-57092-6"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"2759","DOI":"10.1038\/s41467-020-16491-3","article-title":"Human norovirus targets enteroendocrine epithelial cells in the small intestine","volume":"11","author":"Green","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1021\/acs.biochem.8b01063","article-title":"Structural and Antiviral Studies of the Human Norovirus GII.4 Protease","volume":"58","author":"Muzzarelli","year":"2019","journal-title":"Biochemistry"},{"key":"ref_149","doi-asserted-by":"crossref","unstructured":"Viskovska, M.A., Zhao, B., Shanker, S., Choi, J.-M., Deng, L., Song, Y., Palzkill, T., Hu, L., Estes, M.K., and Prasad, B.V.V. (2019). GII.4 Norovirus Protease Shows pH-Sensitive Proteolysis with a Unique Arg-His Pairing in the Catalytic Site. J. Virol., 93.","DOI":"10.1128\/JVI.01479-18"},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Chang, K.O., Kim, Y., Lovell, S., Rathnayake, A.D., and Groutas, W.C. (2019). Antiviral Drug Discovery: Norovirus Proteases and Development of Inhibitors. Viruses, 11.","DOI":"10.3390\/v11020197"},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Abu Bakar, F., and Ng, L.F.P. (2018). Nonstructural Proteins of Alphavirus\u2014Potential Targets for Drug Development. Viruses, 10.","DOI":"10.3390\/v10020071"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.jmb.2010.01.044","article-title":"Frameshifting in alphaviruses: A diversity of 3\u2019 stimulatory structures","volume":"397","author":"Chung","year":"2010","journal-title":"J. Mol. Biol."},{"key":"ref_153","doi-asserted-by":"crossref","unstructured":"Potu\u017en\u00edk, J.F., and Cahov\u00e1, H. (2020). It\u2019s the Little Things (in Viral RNA). mBio, 11.","DOI":"10.1128\/mBio.02131-20"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"2631","DOI":"10.1002\/j.1460-2075.1990.tb07445.x","article-title":"Cleavage-site preferences of Sindbis virus polyproteins containing the non-structural proteinase. Evidence for temporal regulation of polyprotein processing in vivo","volume":"9","author":"Hardy","year":"1990","journal-title":"EMBO J."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/s41586-020-3036-8","article-title":"Capping pores of alphavirus nsP1 gate membranous viral replication factories","volume":"589","author":"Jones","year":"2021","journal-title":"Nature"},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Hellstr\u00f6m, K., Kallio, K., Utt, A., Quirin, T., Jokitalo, E., Merits, A., Ahola, T., and Simon, A.E. (2017). Partially Uncleaved Alphavirus Replicase Forms Spherule Structures in the Presence and Absence of RNA Template. J. Virol., 91.","DOI":"10.1128\/JVI.00787-17"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1128\/jvi.68.3.1874-1885.1994","article-title":"Regulation of Sindbis virus RNA replication: Uncleaved P123 and nsP4 function in minus-strand RNA synthesis, whereas cleaved products from P123 are required for efficient plus-strand RNA synthesis","volume":"68","author":"Shirako","year":"1994","journal-title":"J. Virol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"2925","DOI":"10.1002\/j.1460-2075.1994.tb06587.x","article-title":"Polypeptide requirements for assembly of functional Sindbis virus replication complexes: A model for the temporal regulation of minus- and plus-strand RNA synthesis","volume":"13","author":"Lemm","year":"1994","journal-title":"EMBO J."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"16534","DOI":"10.1073\/pnas.1210418109","article-title":"Structural and functional insights into alphavirus polyprotein processing and pathogenesis","volume":"109","author":"Shin","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"5413","DOI":"10.1128\/JVI.00229-06","article-title":"Molecular determinants of substrate specificity for Semliki Forest virus nonstructural protease","volume":"80","author":"Lulla","year":"2006","journal-title":"J. Virol."},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Lulla, V., Karo-Astover, L., Rausalu, K., Saul, S., Merits, A., and Lulla, A. (2018). Timeliness of Proteolytic Events Is Prerequisite for Efficient Functioning of the Alphaviral Replicase. J. Virol., 92.","DOI":"10.1128\/JVI.00151-18"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/nrmicro.2017.170","article-title":"Rewiring cellular networks by members of the Flaviviridae family","volume":"16","author":"Neufeldt","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/0042-6822(85)90156-4","article-title":"Sequence analysis of the viral core protein and the membrane-associated proteins V1 and NV2 of the flavivirus west nile virus and of the genome sequence for these proteins","volume":"145","author":"Castle","year":"1985","journal-title":"Virology"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/0042-6822(89)90162-1","article-title":"Analyses of the terminal sequences of west nile virus structural proteins and of the in vitro translation of these proteins allow the proposal of a complete scheme of the proteolytic cleavages involved in their synthesis","volume":"169","author":"Nowak","year":"1989","journal-title":"Virology"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1128\/jvi.65.5.2467-2475.1991","article-title":"Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins","volume":"65","author":"Falgout","year":"1991","journal-title":"J. Virol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"3794","DOI":"10.1128\/jvi.68.6.3794-3802.1994","article-title":"NS2B-3 proteinase-mediated processing in the yellow fever virus structural region: In vitro and in vivo studies","volume":"68","author":"Amberg","year":"1994","journal-title":"J. Virol."},{"key":"ref_167","doi-asserted-by":"crossref","unstructured":"Rana, J., and Burrone, O.R. (2019). DENV2 Pseudoviral Particles with Unprocessed Capsid Protein Are Assembled and Infectious. Viruses, 12.","DOI":"10.3390\/v12010027"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.virusres.2012.06.012","article-title":"NS2B\/3 proteolysis at the C-prM junction of the tick-borne encephalitis virus polyprotein is highly membrane dependent","volume":"168","author":"Kurz","year":"2012","journal-title":"Virus Res."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"8475","DOI":"10.1128\/jvi.71.11.8475-8481.1997","article-title":"Proteolytic activation of tick-borne encephalitis virus by furin","volume":"71","author":"Stadler","year":"1997","journal-title":"J. Virol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1126\/science.1153264","article-title":"Structure of the Immature Dengue Virus at Low pH Primes Proteolytic Maturation","volume":"319","author":"Yu","year":"2008","journal-title":"Science"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jsb.2013.11.001","article-title":"Mechanism for maturation-related reorganization of flavivirus glycoproteins","volume":"185","author":"Plevka","year":"2014","journal-title":"J. Struct. Biol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"7622","DOI":"10.1073\/pnas.92.17.7622","article-title":"The hepatitis C virus NS3 serine proteinase and NS4A cofactor: Establishment of a cell-free trans-processing assay","volume":"92","author":"Lin","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/liv.12061","article-title":"New therapeutic strategies in HCV: Second-generation protease inhibitors","volume":"33","author":"Clark","year":"2013","journal-title":"Liver Int."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.biochi.2019.05.004","article-title":"Exploiting the unique features of Zika and Dengue proteases for inhibitor design","volume":"166","author":"Konvalinka","year":"2019","journal-title":"Biochimie"},{"key":"ref_175","doi-asserted-by":"crossref","unstructured":"Li, Q., and Kang, C. (2021). Structure and Dynamics of Zika Virus Protease and Its Insights into Inhibitor Design. Biomedicines, 9.","DOI":"10.3390\/biomedicines9081044"},{"key":"ref_176","doi-asserted-by":"crossref","unstructured":"Gupta, G., Lim, L., and Song, J. (2015). NMR and MD Studies Reveal That the Isolated Dengue NS3 Protease Is an Intrinsically Disordered Chymotrypsin Fold Which Absolutely Requests NS2B for Correct Folding and Functional Dynamics. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134823"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"9963","DOI":"10.1074\/jbc.275.14.9963","article-title":"Purified NS2B\/NS3 Serine Protease of Dengue Virus Type 2 Exhibits Cofactor NS2B Dependence for Cleavage of Substrates with Dibasic Amino Acids","volume":"275","author":"Yusof","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1099\/0022-1317-80-5-1167","article-title":"Homology model of the dengue 2 virus NS3 protease: Putative interactions with both substrate and NS2B cofactor","volume":"80","author":"Brinkworth","year":"1999","journal-title":"J. Gen. Virol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"45762","DOI":"10.1074\/jbc.M107360200","article-title":"Activity of Recombinant Dengue 2 Virus NS3 Protease in the Presence of a Truncated NS2B Co-factor, Small Peptide Substrates, and Inhibitors","volume":"276","author":"Leung","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1126\/science.aag2419","article-title":"Crystal structure of Zika virus NS2B-NS3 protease in complex with a boronate inhibitor","volume":"353","author":"Lei","year":"2016","journal-title":"Science"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.biochi.2020.04.014","article-title":"Conformational selection in the flaviviral NS2B-NS3 protease","volume":"174","author":"Behnam","year":"2020","journal-title":"Biochimie"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.jmb.2007.06.055","article-title":"Crystal Structure and Activity of Kunjin Virus NS3 Helicase; Protease and Helicase Domain Assembly in the Full Length NS3 Protein","volume":"372","author":"Mastrangelo","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"10278","DOI":"10.1128\/JVI.79.16.10278-10288.2005","article-title":"Structure of the Dengue Virus Helicase\/Nucleoside Triphosphatase Catalytic Domain at a Resolution of 2.4 A","volume":"79","author":"Xu","year":"2005","journal-title":"J. Virol."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"18817","DOI":"10.1074\/jbc.M109.090936","article-title":"Flexibility between the protease and helicase domains of the dengue virus NS3 protein conferred by the linker region and its functional implications","volume":"285","author":"Luo","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"6832","DOI":"10.1021\/jacs.9b02505","article-title":"Discovery, X-ray Crystallography and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease","volume":"141","author":"Yao","year":"2019","journal-title":"J. Am. Chem. Soc."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1099\/0022-1317-78-2-337","article-title":"Internal proteolysis of the NS3 protein specified by dengue virus 2","volume":"78","author":"Teo","year":"1997","journal-title":"J. Gen. Virol."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"4773","DOI":"10.1128\/JVI.76.10.4773-4784.2002","article-title":"Mutations in the yellow fever virus nonstructural protein NS2A selectively block production of infectious particles","volume":"76","author":"Rice","year":"2002","journal-title":"J. Virol."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"10136","DOI":"10.1073\/pnas.1805195115","article-title":"Targeting intramolecular proteinase NS2B\/3 cleavages for trans-dominant inhibition of dengue virus","volume":"115","author":"Constant","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.antiviral.2015.03.010","article-title":"Antiviral activities of 15 dengue NS2B-NS3 protease inhibitors using a human cell-based viral quantification assay","volume":"118","author":"Chu","year":"2015","journal-title":"Antivir. Res."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.antiviral.2010.12.006","article-title":"Anthracene-based inhibitors of dengue virus NS2B\u2013NS3 protease","volume":"89","author":"Tomlinson","year":"2011","journal-title":"Antivir. Res."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"113695","DOI":"10.1016\/j.ejmech.2021.113695","article-title":"Amidoxime prodrugs convert to potent cell-active multimodal inhibitors of the dengue virus protease","volume":"224","author":"Swarbrick","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1021\/acsmedchemlett.9b00058","article-title":"Prodrug Activation by a Viral Protease: Evaluating Combretastatin Peptide Hybrids to Selectively Target Infected Cells","volume":"10","author":"Richter","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1128\/JVI.01788-07","article-title":"Crystal structure of the NS3 protease-helicase from dengue virus","volume":"82","author":"Luo","year":"2008","journal-title":"J. Virol."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.virol.2006.02.041","article-title":"Molecular diversity of coronaviruses in bats","volume":"351","author":"Woo","year":"2006","journal-title":"Virology"},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/apm.13047","article-title":"Studies on viral pneumonia related to novel coronavirus SARS-CoV-2, SARS-CoV, and MERS-CoV: A literature review","volume":"128","author":"Liya","year":"2020","journal-title":"APMIS"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"2939","DOI":"10.1099\/0022-1317-69-12-2939","article-title":"Coronaviruses: Structure and Genome Expression","volume":"69","author":"Spaan","year":"1988","journal-title":"J. Gen. Virol."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1126\/science.1085952","article-title":"Characterization of a Novel Coronavirus Associated with Severe Acute Respiratory Syndrome","volume":"300","author":"Rota","year":"2003","journal-title":"Science"},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"5717","DOI":"10.1073\/pnas.0510851103","article-title":"Severe acute respiratory syndrome coronavirus papain-like protease: Structure of a viral deubiquitinating enzyme","volume":"103","author":"Ratia","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"4331","DOI":"10.1128\/jvi.69.7.4331-4338.1995","article-title":"Characterization of a human coronavirus (strain 229E) 3C-like proteinase activity","volume":"69","author":"Ziebuhr","year":"1995","journal-title":"J. Virol."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1126\/science.abf3546","article-title":"Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome","volume":"372","author":"Bhatt","year":"2021","journal-title":"Science"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.virusres.2007.02.015","article-title":"Evaluating the 3C-like protease activity of SARS-Coronavirus: Recommendations for standardized assays for drug discovery","volume":"133","author":"Ratia","year":"2008","journal-title":"Virus Res."},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/s13238-010-0044-8","article-title":"Three-dimensional domain swapping as a mechanism to lock the active conformation in a super-active octamer of SARS-CoV main protease","volume":"1","author":"Zhang","year":"2010","journal-title":"Protein Cell"},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"13894","DOI":"10.1074\/jbc.M510745200","article-title":"Only one protomer is active in the dimer of SARS 3C-like proteinase","volume":"281","author":"Chen","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1126\/science.abb3405","article-title":"Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved \u03b1-ketoamide inhibitors","volume":"368","author":"Zhang","year":"2020","journal-title":"Science"},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1107\/S2052252521001159","article-title":"Crystallographic models of SARS-CoV-2 3CLpro: In-depth assessment of structure quality and validation","volume":"8","author":"Jaskolski","year":"2021","journal-title":"IUCrJ"},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"4889","DOI":"10.1039\/D1SC00145K","article-title":"High-resolution mining of the SARS-CoV-2 main protease conformational space: Supercomputer-driven unsupervised adaptive sampling","volume":"12","author":"Adjoua","year":"2021","journal-title":"Chem. Sci."},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"14908","DOI":"10.1021\/bi0616302","article-title":"Long-range cooperative interactions modulate dimerization in SARS 3CLpro","volume":"45","author":"Barrila","year":"2006","journal-title":"Biochemistry"},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"31257","DOI":"10.1074\/jbc.M502577200","article-title":"Mechanism of the maturation process of SARS-CoV 3CL protease","volume":"280","author":"Hsu","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1111\/febs.12222","article-title":"Autoprocessing mechanism of severe acute respiratory syndrome coronavirus 3C-like protease (SARS-CoV 3CLpro) from its polyproteins","volume":"280","author":"Muramatsu","year":"2013","journal-title":"FEBS J."},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s13238-010-0011-4","article-title":"Liberation of SARS-CoV main protease from the viral polyprotein: N-terminal autocleavage does not depend on the mature dimerization mode","volume":"1","author":"Chen","year":"2010","journal-title":"Protein Cell"},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"167118","DOI":"10.1016\/j.jmb.2021.167118","article-title":"A Crystallographic Snapshot of SARS-CoV-2 Main Protease Maturation Process","volume":"433","author":"Noske","year":"2021","journal-title":"J. Mol. Biol."},{"key":"ref_212","doi-asserted-by":"crossref","unstructured":"Roe, M.K., Junod, N.A., Young, A.R., Beachboard, D.C., and Stobart, C.C. (2021). Targeting novel structural and functional features of coronavirus protease nsp5 (3CLpro, Mpro) in the age of COVID-19. J. Gen. Virol., 102.","DOI":"10.1099\/jgv.0.001558"},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"5877","DOI":"10.1038\/s41467-020-19662-4","article-title":"Crystallographic structure of wild-type SARS-CoV-2 main protease acyl-enzyme intermediate with physiological C-terminal autoprocessing site","volume":"11","author":"Lee","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1074\/jbc.M310875200","article-title":"Biosynthesis, Purification, and Substrate Specificity of Severe Acute Respiratory Syndrome Coronavirus 3C-like Proteinase","volume":"279","author":"Fan","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"4620","DOI":"10.1128\/JVI.02680-07","article-title":"Mechanism for Controlling the Dimer-Monomer Switch and Coupling Dimerization to Catalysis of the Severe Acute Respiratory Syndrome Coronavirus 3C-Like Protease","volume":"82","author":"Shi","year":"2008","journal-title":"J. Virol."},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1016\/j.bpj.2009.12.4272","article-title":"Mutation of Glu-166 blocks the substrate-induced dimerization of SARS coronavirus main protease","volume":"98","author":"Cheng","year":"2010","journal-title":"Biophys. J."},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"4281","DOI":"10.1128\/JVI.02869-12","article-title":"Structural basis of substrate specificity and protease inhibition in Norwalk virus","volume":"87","author":"Muhaxhiri","year":"2013","journal-title":"J. Virol."},{"key":"ref_218","doi-asserted-by":"crossref","unstructured":"Ingr, M., Lange, R., Halabalov\u00e1, V., Yehya, A., Hrn\u010di\u0159\u00edk, J., Chevalier-Lucia, D., Palmade, L., Blayo, C., Konvalinka, J., and Dumay, E. (2015). Inhibitor and substrate binding induced stability of HIV-1 protease against sequential dissociation and unfolding revealed by high pressure spectroscopy and kinetics. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119099"},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1111\/j.1742-4658.2006.05130.x","article-title":"The catalysis of the SARS 3C-like protease is under extensive regulation by its extra domain","volume":"273","author":"Shi","year":"2006","journal-title":"FEBS J."},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.pbiomolbio.2018.08.009","article-title":"Structurally- and dynamically-driven allostery of the chymotrypsin-like proteases of SARS, Dengue and Zika viruses","volume":"143","author":"Lim","year":"2019","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.csbj.2020.03.017","article-title":"The impact of tunnel mutations on enzymatic catalysis depends on the tunnel-substrate complementarity and the rate-limiting step","volume":"18","author":"Kokkonen","year":"2020","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_222","doi-asserted-by":"crossref","unstructured":"Rathnayake, A.D., Zheng, J., Kim, Y., Perera, K.D., Mackin, S., Meyerholz, D.K., Kashipathy, M.M., Battaile, K.P., Lovell, S., and Perlman, S. (2020). 3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV\u2013infected mice. Sci. Transl. Med., 12.","DOI":"10.1126\/scitranslmed.abc5332"},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"4942","DOI":"10.1128\/JVI.03688-14","article-title":"Broad-spectrum inhibitors against 3C-like proteases of feline coronaviruses and feline caliciviruses","volume":"89","author":"Kim","year":"2015","journal-title":"J. Virol."},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"4282","DOI":"10.1038\/s41467-020-18096-2","article-title":"Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication","volume":"11","author":"Vuong","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_225","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.coviro.2021.04.006","article-title":"Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection","volume":"49","author":"Vandyck","year":"2021","journal-title":"Curr. Opin. Virol."},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1126\/science.abf7945","article-title":"X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease","volume":"372","author":"Reinke","year":"2021","journal-title":"Science"},{"key":"ref_227","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1021\/acscentsci.0c01186","article-title":"Simeprevir Potently Suppresses SARS-CoV-2 Replication and Synergizes with Remdesivir","volume":"7","author":"Lo","year":"2021","journal-title":"ACS Cent. Sci."},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/s42003-020-01577-x","article-title":"Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents","volume":"4","author":"Mody","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1126\/science.abg5827","article-title":"Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2","volume":"373","author":"Drayman","year":"2021","journal-title":"Science"},{"key":"ref_230","doi-asserted-by":"crossref","first-page":"111313","DOI":"10.1016\/j.biopha.2021.111313","article-title":"An update review of emerging small-molecule therapeutic options for COVID-19","volume":"137","author":"Tian","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_231","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1039\/D1MD00066G","article-title":"A review of the latest research on M(pro) targeting SARS-COV inhibitors","volume":"12","author":"Yang","year":"2021","journal-title":"RSC Med. Chem."},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"23544","DOI":"10.1002\/anie.202010316","article-title":"Allosteric Inhibition of the SARS-CoV-2 Main Protease: Insights from Mass Spectrometry Based Assays","volume":"59","author":"Lutomski","year":"2020","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"3623","DOI":"10.1038\/s41467-021-23751-3","article-title":"Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease","volume":"12","author":"Su","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_234","doi-asserted-by":"crossref","unstructured":"Rizzuti, B., Grande, F., Conforti, F., Jimenez-Alesanco, A., Ceballos-Laita, L., Ortega-Alarcon, D., Vega, S., Reyburn, H.T., Abian, O., and Velazquez-Campoy, A. (2021). Rutin Is a Low Micromolar Inhibitor of SARS-CoV-2 Main Protease 3CLpro: Implications for Drug Design of Quercetin Analogs. Biomedicines, 9.","DOI":"10.3390\/biomedicines9040375"},{"key":"ref_235","doi-asserted-by":"crossref","unstructured":"Rizzuti, B., Ceballos-Laita, L., Ortega-Alarcon, D., Jimenez-Alesanco, A., Vega, S., Grande, F., Conforti, F., Abian, O., and Velazquez-Campoy, A. (2021). Sub-Micromolar Inhibition of SARS-CoV-2 3CLpro by Natural Compounds. Pharmaceuticals, 14.","DOI":"10.3390\/ph14090892"},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"6799","DOI":"10.1002\/anie.202016113","article-title":"Ligand Selection Strategy Identifies Chemical Probes Targeting the Proteases of SARS-CoV-2","volume":"60","author":"Schmid","year":"2021","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_237","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1016\/j.str.2020.10.007","article-title":"Malleability of the SARS-CoV-2 3CL M(pro) Active-Site Cavity Facilitates Binding of Clinical Antivirals","volume":"28","author":"Kneller","year":"2020","journal-title":"Structure"},{"key":"ref_238","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.biochi.2021.01.010","article-title":"Protein structural heterogeneity: A hypothesis for the basis of proteolytic recognition by the main protease of SARS-CoV and SARS-CoV-2","volume":"182","author":"Behnam","year":"2021","journal-title":"Biochimie"},{"key":"ref_239","doi-asserted-by":"crossref","first-page":"13722","DOI":"10.1128\/JVI.02271-14","article-title":"Induced maturation of human immunodeficiency virus","volume":"88","author":"Mattei","year":"2014","journal-title":"J. Virol."},{"key":"ref_240","doi-asserted-by":"crossref","unstructured":"Klemm, T., Ebert, G., Calleja, D.J., Allison, C.C., Richardson, L.W., Bernardini, J.P., Lu, B.G., Kuchel, N.W., Grohmann, C., and Shibata, Y. (2020). Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2. EMBO J., 39.","DOI":"10.15252\/embj.2020106275"},{"key":"ref_241","doi-asserted-by":"crossref","first-page":"13600","DOI":"10.1128\/JVI.78.24.13600-13612.2004","article-title":"Identification of severe acute respiratory syndrome coronavirus replicase products and characterization of papain-like protease activity","volume":"78","author":"Harcourt","year":"2004","journal-title":"J. Virol."},{"key":"ref_242","doi-asserted-by":"crossref","first-page":"7911","DOI":"10.1128\/JVI.74.17.7911-7921.2000","article-title":"Identification of mouse hepatitis virus papain-like proteinase 2 activity","volume":"74","author":"Kanjanahaluethai","year":"2000","journal-title":"J. Virol."},{"key":"ref_243","doi-asserted-by":"crossref","unstructured":"Sawicki, S.G., Sawicki, D.L., Younker, D., Meyer, Y., Thiel, V., Stokes, H., and Siddell, S.G. (2005). Functional and Genetic Analysis of Coronavirus Replicase-Transcriptase Proteins. PLoS Pathog., 1.","DOI":"10.1371\/journal.ppat.0010039"},{"key":"ref_244","doi-asserted-by":"crossref","first-page":"15189","DOI":"10.1128\/JVI.79.24.15189-15198.2005","article-title":"The Papain-Like Protease of Severe Acute Respiratory Syndrome Coronavirus Has Deubiquitinating Activity","volume":"79","author":"Barretto","year":"2005","journal-title":"J. Virol."},{"key":"ref_245","doi-asserted-by":"crossref","first-page":"6007","DOI":"10.1128\/JVI.02747-06","article-title":"Proteolytic Processing and Deubiquitinating Activity of Papain-Like Proteases of Human Coronavirus NL63","volume":"81","author":"Chen","year":"2007","journal-title":"J. Virol."},{"key":"ref_246","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/s41586-020-2601-5","article-title":"Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity","volume":"587","author":"Shin","year":"2020","journal-title":"Nature"},{"key":"ref_247","doi-asserted-by":"crossref","unstructured":"Yan, S., and Wu, G. (2021). Spatial and temporal roles of SARS-CoV PLpro\u2014A snapshot. FASEB J., 35.","DOI":"10.1096\/fj.202002271"},{"key":"ref_248","doi-asserted-by":"crossref","unstructured":"Cihlova, B., Huskova, A., B\u00f6serle, J., Nencka, R., Boura, E., and Silhan, J. (2021). High-Throughput Fluorescent Assay for Inhibitor Screening of Proteases from RNA Viruses. Molecules, 26.","DOI":"10.3390\/molecules26133792"},{"key":"ref_249","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.antiviral.2017.12.015","article-title":"Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes","volume":"150","author":"Lin","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_250","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.jmgm.2017.05.013","article-title":"Specific interactions between zinc metalloproteinase anditsinhibitors: Ab initio fragment molecular orbital calculations","volume":"75","author":"Ara","year":"2017","journal-title":"J. Mol. Graph. Model."},{"key":"ref_251","doi-asserted-by":"crossref","unstructured":"Armstrong, L.A., Lange, S.M., Dee Cesare, V., Matthews, S.P., Nirujogi, R.S., Cole, I., Hope, A., Cunningham, F., Toth, R., and Mukherjee, R. (2021). Biochemical characterization of protease activity of Nsp3 from SARS-CoV-2 and its inhibition bynanobodies. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0253364"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/10\/1981\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:08:47Z","timestamp":1760166527000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/10\/1981"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,2]]},"references-count":251,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["v13101981"],"URL":"https:\/\/doi.org\/10.3390\/v13101981","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,2]]}}}