{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T10:06:59Z","timestamp":1792058819485,"version":"4.4.0"},"reference-count":79,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T00:00:00Z","timestamp":1713225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PRIN2022_PNRR","award":["P2022KCW3L"],"award-info":[{"award-number":["P2022KCW3L"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In the global pandemic scenario, dengue and zika viruses (DENV and ZIKV, respectively), both mosquito-borne members of the flaviviridae family, represent a serious health problem, and considering the absence of specific antiviral drugs and available vaccines, there is a dire need to identify new targets to treat these types of viral infections. Within this drug discovery process, the protease NS2B\/NS3 is considered the primary target for the development of novel anti-flavivirus drugs. The NS2B\/NS3 is a serine protease that has a dual function both in the viral replication process and in the elusion of the innate immunity. To date, two main classes of NS2B\/NS3 of DENV and ZIKV protease inhibitors have been discovered: those that bind to the orthosteric site and those that act at the allosteric site. Therefore, this perspective article aims to discuss the main features of the use of the most potent NS2B\/NS3 inhibitors and their impact at the social level.<\/jats:p>","DOI":"10.3390\/ijms25084376","type":"journal-article","created":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T04:21:59Z","timestamp":1713241319000},"page":"4376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["The Inhibition of NS2B\/NS3 Protease: A New Therapeutic Opportunity to Treat Dengue and Zika Virus Infection"],"prefix":"10.3390","volume":"25","author":[{"given":"Jos\u00e8","family":"Starvaggi","sequence":"first","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8473-3321","authenticated-orcid":false,"given":"Santo","family":"Previti","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8942-797X","authenticated-orcid":false,"given":"Maria","family":"Zappal\u00e0","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9020-2068","authenticated-orcid":false,"given":"Roberta","family":"Ettari","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,16]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2023, December 15). Dengue and Severe Dengue, Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/dengue-and-severe-dengue."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3963","DOI":"10.1016\/j.bmc.2019.07.038","article-title":"Peptide derivatives as inhibitors of NS2B-NS3 protease from Dengue, West Nile, and Zika flaviviruses","volume":"27","year":"2019","journal-title":"Bioorg. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00284-020-02284-w","article-title":"Current understanding of the pathogenesis of Dengue virus infection","volume":"78","author":"Bhatt","year":"2021","journal-title":"Curr. Microbiol."},{"key":"ref_4","unstructured":"World Health Organization (2023, December 15). Zika Virus, Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/zika-virus."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"433","DOI":"10.4103\/ijmr.IJMR_169_20","article-title":"Molecular mechanisms of Zika virus pathogenesis: An update","volume":"154","author":"Bhagat","year":"2021","journal-title":"Indian J. Med. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2744","DOI":"10.1021\/cb400612h","article-title":"Allosteric inhibition of the NS2B-NS3 protease from Dengue virus","volume":"8","author":"Yildiz","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Gangopadhyay, A., and Saha, A. (2023). Exploring allosteric hits of the NS2B-NS3 protease of DENV2 by structure-guided screening. Comput. Biol. Chem., 104.","DOI":"10.1016\/j.compbiolchem.2023.107876"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wahaab, A., Mustafa, B.E., Hameed, M., Stevenson, N.J., Anwar, M.N., Liu, K., Wei, J., Qiu, Y., and Ma, Z. (2021). Potential role of flavivirus NS2B-NS3 proteases in viral pathogenesis and anti-flavivirus drug discovery employing animal cells and models: A review. Viruses, 14.","DOI":"10.3390\/v14010044"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1128\/JVI.06225-11","article-title":"Ligand-bound structures of the dengue virus protease reveal the active conformation","volume":"86","author":"Noble","year":"2012","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1021\/acsmedchemlett.9b00405","article-title":"Discovery of Zika virus NS2B\/NS3 inhibitors that prevent mice from life-threatening infection and brain damage","volume":"11","author":"Coluccia","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Voss, S., and Nitsche, C. (2020). Inhibitors of the Zika virus protease NS2B-NS3. Bioorg. Med. Chem. Lett., 30.","DOI":"10.1016\/j.bmcl.2020.126965"},{"key":"ref_12","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_13","doi-asserted-by":"crossref","unstructured":"Meewan, I., Shiryaev, S.A., Kattoula, J., Huang, C.T., Lin, V., Chuang, C.H., Terskikh, A.V., and Abagyan, R. (2023). Allosteric inhibitors of Zika virus NS2B-NS3 protease targeting protease in \u201csuper-open\u201d conformation. Viruses, 15.","DOI":"10.3390\/v15051106"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17345","DOI":"10.1073\/pnas.1010811107","article-title":"Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis","volume":"107","author":"Heaton","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.1038\/s41598-019-39157-7","article-title":"Dengue virus nonstructural 3 protein interacts directly with human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and reduces its glycolytic activity","volume":"9","author":"Silva","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3762","DOI":"10.1158\/0008-5472.CAN-04-3954","article-title":"Glyceraldehyde-3-phosphate dehydrogenase binds to the AU-Rich 3\u2019 untranslated region of colony-stimulating factor-1 (CSF-1) messenger RNA in human ovarian cancer cells: Possible role in CSF-1 posttranscriptional regulation and tumor phenotype","volume":"65","author":"Bonafe","year":"2005","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.abb.2012.09.004","article-title":"Glyceraldehyde-3-phosphate dehydrogenase regulates cyclooxygenase-2 expression by targeting mRNA stability","volume":"528","author":"Ikeda","year":"2012","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1080\/15548627.2016.1265192","article-title":"Dengue and Zika viruses subvert reticulophagy by NS2B3-mediated cleavage of FAM134B","volume":"13","author":"Lennemann","year":"2017","journal-title":"Autophagy"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1016\/j.neuron.2019.01.010","article-title":"Zika virus protease cleavage of host protein septin-2 mediates mitotic defects in neural progenitors","volume":"101","author":"Li","year":"2019","journal-title":"Neuron"},{"key":"ref_20","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_21","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1007\/s12250-013-3390-x","article-title":"The flavivirus protease as a target for drug discovery","volume":"28","author":"Brecher","year":"2013","journal-title":"Virol. Sin."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.antiviral.2018.10.006","article-title":"Structures of Zika virus NS2B-NS3 protease in complex with peptidomimetic inhibitors","volume":"160","author":"Phoo","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.antiviral.2017.04.015","article-title":"Characterization of the Zika virus two-component NS2B-NS3 protease and structure-assisted identification of allosteric small-molecule antagonists","volume":"143","author":"Shiryaev","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1126\/science.aai9309","article-title":"Crystal structure of unlinked NS2B-NS3 protease from Zika virus","volume":"354","author":"Zhang","year":"2016","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1007\/s13238-016-0275-4","article-title":"The crystal structure of Zika virus helicase: Basis for antiviral drug design","volume":"7","author":"Tian","year":"2016","journal-title":"Protein Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13410","DOI":"10.1038\/ncomms13410","article-title":"Structure of the NS2B-NS3 protease from Zika virus after self-cleavage","volume":"7","author":"Phoo","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_27","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_28","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1110\/ps.072753207","article-title":"Structural evidence for regulation and specificity of flaviviral proteases and evolution of the Flaviviridae fold","volume":"16","author":"Aleshin","year":"2007","journal-title":"Protein Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1128\/JVI.02044-09","article-title":"Serotype-specific structural differences in the protease-cofactor complexes of the dengue virus family","volume":"84","author":"Chandramouli","year":"2010","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.pep.2011.08.008","article-title":"Expression, purification, and initial structural characterization of nonstructural protein 2B, an integral membrane protein of Dengue-2 virus, in detergent micelles","volume":"80","author":"Huang","year":"2011","journal-title":"Protein Expr. Purif."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.pep.2013.09.015","article-title":"Lyso-myristoyl phosphatidylcholine micelles sustain the activity of Dengue non-structural (NS) protein 3 protease domain fused with the full-length NS2B","volume":"92","author":"Huang","year":"2013","journal-title":"Protein Expr. Purif."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.pep.2016.02.001","article-title":"Selection of suitable detergents for obtaining an active dengue protease in its natural form from E. coli","volume":"121","author":"Liew","year":"2016","journal-title":"Protein Expr. Purif."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pep.2018.09.013","article-title":"Expression, purification of Zika virus membrane protein-NS2B in detergent micelles for NMR studies","volume":"154","author":"Ng","year":"2019","journal-title":"Protein Expr. Purif."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.pep.2015.11.022","article-title":"Simultaneous uncoupled expression and purification of the Dengue virus NS3 protease and NS2B co-factor domain","volume":"119","author":"Shannon","year":"2016","journal-title":"Protein Expr. Purif."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3422","DOI":"10.2174\/13816128113199990633","article-title":"Drug design for flavivirus proteases: What are we missing?","volume":"20","author":"Poulsen","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/nsmb1073","article-title":"Structural basis for the activation of flaviviral NS3 proteases from dengue and West Nile virus","volume":"13","author":"Erbel","year":"2006","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1099\/vir.0.83359-0","article-title":"Structure-based mutagenesis identifies important novel determinants of the NS2B cofactor of the West Nile virus two-component NS2B-NS3 proteinase","volume":"89","author":"Radichev","year":"2008","journal-title":"J. Gen. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1099\/vir.0.83447-0","article-title":"Mutagenesis of the West Nile virus NS2B cofactor domain reveals two regions essential for protease activity","volume":"89","author":"Chappell","year":"2008","journal-title":"J. Gen. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Li, Q., and Kang, C. (2020). Insights into Structures and Dynamics of Flavivirus Proteases from NMR Studies. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072527"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11359","DOI":"10.1021\/acs.jmedchem.9b01697","article-title":"Proline-based allosteric inhibitors of Zika and Dengue Virus NS2B\/NS3 proteases","volume":"62","author":"Millies","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Maus, H., Barthels, F., Hammerschmidt, S.J., Kopp, K., Millies, B., Gellert, A., Ruggieri, A., and Schirmeister, T. (2021). SAR of novel benzothiazoles targeting an allosteric pocket of DENV and ZIKV NS2B\/NS3 proteases. Bioorg. Med. Chem., 47.","DOI":"10.1016\/j.bmc.2021.116392"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1128\/JVI.01325-08","article-title":"Mechanism of NS2B-mediated activation of NS3pro in Dengue virus: Molecular dynamics simulations and bioassays","volume":"83","author":"Zuo","year":"2009","journal-title":"J. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1021\/acsmedchemlett.8b00316","article-title":"One step beyond: Design of substrates spanning primed positions of Zika virus NS2B-NS3 protease","volume":"9","author":"Gruba","year":"2018","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_44","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":"Majerova","year":"2019","journal-title":"Biochimie"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5172","DOI":"10.1021\/acs.jmedchem.5b01697","article-title":"Recent progress in the development of HIV-1 protease inhibitors for the treatment of HIV\/AIDS","volume":"59","author":"Ghosh","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.bmcl.2005.09.062","article-title":"Peptide inhibitors of Dengue virus NS3 protease. Part 1: Warhead","volume":"16","author":"Yin","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.bmcl.2005.09.049","article-title":"Peptide inhibitors of Dengue virus NS3 protease. Part 2: SAR study of tetrapeptide aldehyde inhibitors","volume":"16","author":"Yin","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1021\/acs.jmedchem.6b01021","article-title":"Peptide-boronic acid inhibitors of flaviviral proteases: Medicinal chemistry and structural biology","volume":"60","author":"Nitsche","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4067","DOI":"10.1016\/j.bmc.2011.05.015","article-title":"Synthesis and biological evaluation of alpha-ketoamides as inhibitors of the Dengue virus protease with antiviral activity in cell-culture","volume":"19","author":"Steuer","year":"2011","journal-title":"Bioorg. Med. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7318","DOI":"10.1016\/j.bmc.2011.10.061","article-title":"Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases","volume":"19","author":"Nitsche","year":"2011","journal-title":"Bioorg. Med. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.antiviral.2012.02.008","article-title":"Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease","volume":"94","author":"Nitsche","year":"2012","journal-title":"Antivir. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/S0167-7799(00)88999-4","article-title":"Recent developments in retro peptides and proteins: An ongoing topochemical exploration","volume":"13","author":"Chorev","year":"1995","journal-title":"Trends Biotechnol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6446","DOI":"10.1038\/s41598-018-24517-6","article-title":"Immunosilencing peptides by stereochemical inversion and sequence reversal: Retro-D-peptides","volume":"8","author":"Ciudad","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6549","DOI":"10.1016\/j.bmcl.2013.10.071","article-title":"Discovery and SAR studies of methionine-proline anilides as Dengue virus NS2B-NS3 protease inhibitors","volume":"23","author":"Zhou","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/j.ejmech.2016.09.063","article-title":"Identification of fused bicyclic derivatives of pyrrolidine and imidazolidinone as Dengue virus-2 NS2B-NS3 protease inhibitors","volume":"125","author":"Weng","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.bbrc.2013.03.139","article-title":"Design and evaluation of substrate-based octapeptide and non substrate-based tetrapeptide inhibitors of dengue virus NS2B-NS3 proteases","volume":"434","author":"Prusis","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"9369","DOI":"10.1016\/j.bmc.2008.08.081","article-title":"Proteochemometrics analysis of substrate interactions with Dengue virus NS3 proteases","volume":"16","author":"Prusis","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"8389","DOI":"10.1021\/jm400828u","article-title":"Thiazolidinone-peptide hybrids as dengue virus protease inhibitors with antiviral activity in cell culture","volume":"56","author":"Nitsche","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1021\/ml500245v","article-title":"C-terminal residue optimization and fragment merging: Discovery of a potent peptide-hybrid inhibitor of Dengue protease","volume":"5","author":"Behnam","year":"2014","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5748","DOI":"10.1016\/j.bmc.2015.07.012","article-title":"Dual inhibitors of the dengue and West Nile virus NS2B-NS3 proteases: Synthesis, biological evaluation and docking studies of novel peptide-hybrids","volume":"23","author":"Behnam","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"9354","DOI":"10.1021\/acs.jmedchem.5b01441","article-title":"Discovery of nanomolar Dengue and West Nile virus protease inhibitors containing a 4-benzyloxyphenylglycine residue","volume":"58","author":"Behnam","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"7719","DOI":"10.1021\/acs.jmedchem.5b00612","article-title":"Phenylalanine and phenylglycine analogues as arginine mimetics in Dengue protease inhibitors","volume":"58","author":"Weigel","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"28766","DOI":"10.1074\/jbc.M500588200","article-title":"Functional profiling of recombinant NS3 proteases from all four serotypes of Dengue virus using tetrapeptide and octapeptide substrate libraries","volume":"280","author":"Li","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5714","DOI":"10.1021\/jm800503y","article-title":"Potent cationic inhibitors of West Nile virus NS2B\/NS3 protease with serum stability, cell permeability and antiviral activity","volume":"51","author":"Stoermer","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.antiviral.2011.07.002","article-title":"Tripeptide inhibitors of Dengue and West Nile virus NS2B-NS3 protease","volume":"92","author":"Schuller","year":"2011","journal-title":"Antivir. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"6881","DOI":"10.1021\/jm300655h","article-title":"Critical effect of peptide cyclization on the potency of peptide inhibitors against Dengue virus NS2B-NS3 protease","volume":"55","author":"Xu","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1152\/physrev.00020.2003","article-title":"Conus venoms: A rich source of novel ion channel-targeted peptides","volume":"84","author":"Terlau","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_68","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_69","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1038\/nrd2590","article-title":"The exploration of macrocycles for drug discovery\u2014an underexploited structural class","volume":"7","author":"Driggers","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.addr.2016.03.013","article-title":"Cell permeability beyond the rule of 5","volume":"101","author":"Matsson","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3586","DOI":"10.1016\/j.bmcl.2017.05.027","article-title":"Discovery of novel cyclic peptide inhibitors of Dengue virus NS2B-NS3 protease with antiviral activity","volume":"27","author":"Takagi","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"8899","DOI":"10.1021\/bi980313v","article-title":"Product inhibition of the hepatitis C virus NS3 protease","volume":"37","author":"Steinkuhler","year":"1998","journal-title":"Biochemistry"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"8906","DOI":"10.1021\/bi980314n","article-title":"Potent peptide inhibitors of human hepatitis C virus NS3 protease are obtained by optimizing the cleavage products","volume":"37","author":"Ingallinella","year":"1998","journal-title":"Biochemistry"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1016\/j.bbrc.2005.03.107","article-title":"Competitive inhibition of the dengue virus NS3 serine protease by synthetic peptides representing polyprotein cleavage sites","volume":"330","author":"Chanprapaph","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1021\/acsinfecdis.6b00131","article-title":"Dengue protease substrate recognition: Binding of the prime side","volume":"2","author":"Lin","year":"2016","journal-title":"ACS Infect. Dis."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1016\/j.str.2017.06.006","article-title":"Structural dynamics of Zika virus NS2B-NS3 protease binding to dipeptide inhibitors","volume":"25","author":"Li","year":"2017","journal-title":"Structure"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Sylte, I., Dawadi, R., Malla, N., von Hofsten, S., Nguyen, T.M., Solli, A.I., Berg, E., Adekoya, O.A., Svineng, G., and Winberg, J.O. (2018). The selectivity of galardin and an azasugar-based hydroxamate compound for human matrix metalloproteases and bacterial metalloproteases. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0200237"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1146\/annurev-biochem-060713-035456","article-title":"Selection-based discovery of druglike macrocyclic peptides","volume":"83","author":"Passioura","year":"2014","journal-title":"Annu. Rev. Biochem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.biotechadv.2018.01.004","article-title":"Designing improved active peptides for therapeutic approaches against infectious diseases","volume":"36","author":"Gomes","year":"2018","journal-title":"Biotechnol. 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