{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:00:34Z","timestamp":1787029234856,"version":"build-2736575974"},"reference-count":106,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Emerging mosquito-borne flaviviruses, such as Dengue virus (DENV) and Zika virus (ZIKV), pose major global public health threats due to their geographic expansion, climate change, and the absence of effective antiviral therapies. Antiviral development against these pathogens has primarily focused on two complementary strategies. On the one hand, the blocking of viral replication by directly inhibiting essential viral enzymes, and on the other, enhancing the host\u2019s innate immune defenses via targeted activation of intracellular antiviral pathways. Among the viral proteins required for replication, the NS2B\u2013NS3 protease complex is one of the most conserved and druggable targets, prompting extensive efforts to design both covalent and non-covalent inhibitors. Covalent inhibitors, such as boronic acids, aldehydes, trifluoromethyl ketones, phenoxymethylphenyl derivatives, and \u03b1-ketoamides, form irreversible or slowly reversible bonds with the catalytic serine residue (Ser 135), producing long-lasting and high-affinity suppression of protease activity. In parallel, several classes of non-covalent, particularly allosteric, inhibitors have emerged as promising alternatives with improved specificity and reduced off-target reactivity. A complementary antiviral strategy involves the use of agonists of key innate immune sensors such as TLRs, RIG-I, and the cGAS\u2013STING axis, which mediate the release of interferons (IFNs). This review brings together current knowledge on these two mechanistically distinct yet convergent approaches, highlighting how both can ultimately restrict flavivirus replication. Future opportunities involving modified peptide scaffolds, advanced delivery systems, and drug-repurposing strategies are finally discussed for the development of next-generation therapeutics against DENV and ZIKV.<\/jats:p>","DOI":"10.3390\/pathogens15020232","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T15:57:29Z","timestamp":1771516649000},"page":"232","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Protease Inhibitors and Innate Immune Agonists as Antiviral Strategies Against Dengue and Zika Viruses"],"prefix":"10.3390","volume":"15","author":[{"given":"Marianna","family":"Costa","sequence":"first","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno d\u2019Alcontres 31, 98166 Messina, Italy"},{"name":"Department of Chemistry, Biology, and Biotechnology, University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Trischitta","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno d\u2019Alcontres 31, 98166 Messina, Italy"},{"name":"Department of Chemistry, Biology, and Biotechnology, University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica Mastrolembo","family":"Barn\u00e0","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno d\u2019Alcontres 31, 98166 Messina, Italy"},{"name":"Department of Chemistry, Biology, and Biotechnology, University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8519-7724","authenticated-orcid":false,"given":"Maria Teresa","family":"Sciortino","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno d\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3474-6057","authenticated-orcid":false,"given":"Rosamaria","family":"Pennisi","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno d\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/S0140-6736(08)60238-X","article-title":"Pathogenic Flaviviruses","volume":"371","author":"Gould","year":"2008","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1038\/s41564-020-0714-0","article-title":"The Continued Threat of Emerging Flaviviruses","volume":"5","author":"Pierson","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The Global Distribution and Burden of Dengue","volume":"496","author":"Bhatt","year":"2013","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lowe, R., Gasparrini, A., Van Meerbeeck, C.J., Lippi, C.A., Mahon, R., Trotman, A.R., Rollock, L., Hinds, A.Q.J., Ryan, S.J., and Stewart-Ibarra, A.M. (2018). Nonlinear and Delayed Impacts of Climate on Dengue Risk in Barbados: A Modelling Study. PLoS Med., 15.","DOI":"10.1371\/journal.pmed.1002613"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Johansson, M.A., Dominici, F., and Glass, G.E. (2009). Local and Global Effects of Climate on Dengue Transmission in Puerto Rico. PLoS Negl. Trop. Dis., 3.","DOI":"10.1371\/journal.pntd.0000382"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"102841","DOI":"10.1016\/j.tmaid.2025.102841","article-title":"The Impact of Climate Change on Travel-Related Vector-Borne Diseases: A Case Study on Dengue Virus Transmission","volume":"65","author":"Abbasi","year":"2025","journal-title":"Travel Med. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S897","DOI":"10.1093\/infdis\/jix511","article-title":"Neurological Implications of Zika Virus Infection in Adults","volume":"216","author":"Parra","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1016\/S0140-6736(14)61060-6","article-title":"Clinical Efficacy and Safety of a Novel Tetravalent Dengue Vaccine in Healthy Children in Asia: A Phase 3, Randomised, Observer-Masked, Placebo-Controlled Trial","volume":"384","author":"Capeding","year":"2014","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1056\/NEJMoa1411037","article-title":"Efficacy of a Tetravalent Dengue Vaccine in Children in Latin America","volume":"372","author":"Villar","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e019368","DOI":"10.1136\/bmjopen-2017-019368","article-title":"Efficacy, Immunogenicity and Safety of a Recombinant Tetravalent Dengue Vaccine (CYD-TDV) in Children Aged 2\u201317 Years: Systematic Review and Meta-Analysis","volume":"9","author":"Rosa","year":"2019","journal-title":"BMJ Open"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1056\/NEJMoa1903869","article-title":"Efficacy of a Tetravalent Dengue Vaccine in Healthy Children and Adolescents","volume":"381","author":"Biswal","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100604","DOI":"10.1016\/j.jvacx.2024.100604","article-title":"Current Status of the Development of Dengue Vaccines","volume":"22","author":"Lee","year":"2025","journal-title":"Vaccine X"},{"key":"ref_13","first-page":"5","article-title":"Dengue Dynamics: A Global Update","volume":"14","author":"Yousuf","year":"2023","journal-title":"Adv. Hum. Biol."},{"key":"ref_14","first-page":"100777","article-title":"Effectiveness of Mass Dengue Vaccination with CYD-TDV (Dengvaxia\u00ae) in the State of Paran\u00e1, Brazil: Integrating Case-Cohort and Case-Control Designs","volume":"35","author":"Raboni","year":"2024","journal-title":"Lancet Reg. Health\u2014Am."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7100","DOI":"10.1016\/j.vaccine.2015.09.108","article-title":"Development of the Sanofi Pasteur Tetravalent Dengue Vaccine: One More Step Forward","volume":"33","author":"Guy","year":"2015","journal-title":"Vaccine"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4113","DOI":"10.1016\/j.vaccine.2008.05.058","article-title":"\u201cGuidelines for the Clinical Evaluation of Dengue Vaccines in Endemic Areas\u201d: Summary of a World Health Organization Technical Consultation","volume":"26","author":"Edelman","year":"2008","journal-title":"Vaccine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1016\/S0140-6736(12)61428-7","article-title":"Protective Efficacy of the Recombinant, Live-Attenuated, CYD Tetravalent Dengue Vaccine in Thai Schoolchildren: A Randomised, Controlled Phase 2b Trial","volume":"380","author":"Sabchareon","year":"2012","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1080\/21645515.2019.1658503","article-title":"A Review of Dengvaxia\u00ae: Development to Deployment","volume":"15","author":"Thomas","year":"2019","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1080\/21645515.2018.1522468","article-title":"Vaccine Confidence Plummets in the Philippines Following Dengue Vaccine Scare: Why It Matters to Pandemic Preparedness","volume":"15","author":"Larson","year":"2019","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11436","DOI":"10.1128\/JVI.77.21.11436-11447.2003","article-title":"Dengue 2 PDK-53 Virus as a Chimeric Carrier for Tetravalent Dengue Vaccine Development","volume":"77","author":"Huang","year":"2003","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3011","DOI":"10.1128\/JVI.74.7.3011-3019.2000","article-title":"Attenuation Markers of a Candidate Dengue Type 2 Vaccine Virus, Strain 16681 (PDK-53), Are Defined by Mutations in the 5\u2032 Noncoding Region and Nonstructural Proteins 1 and 3","volume":"74","author":"Butrapet","year":"2000","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1038\/s41541-021-00340-5","article-title":"Attenuated Dengue Viruses Are Genetically More Diverse Than Their Respective Wild-Type Parents","volume":"6","author":"Bifani","year":"2021","journal-title":"NPJ Vaccines"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"978","DOI":"10.4269\/ajtmh.2011.10-0592","article-title":"Efficacy of a Tetravalent Chimeric Dengue Vaccine (DENVax) in Cynomolgus Macaques","volume":"84","author":"Osorio","year":"2011","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e1350","DOI":"10.1093\/cid\/ciac418","article-title":"Clinical Safety Experience of TAK-003 for Dengue Fever: A New Tetravalent Live Attenuated Vaccine Candidate","volume":"76","author":"Patel","year":"2023","journal-title":"Clin. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1093\/cid\/ciab864","article-title":"Three-Year Efficacy and Safety of Takeda\u2019s Dengue Vaccine Candidate (TAK-003)","volume":"75","author":"Rivera","year":"2022","journal-title":"Clin. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1093\/infdis\/jiaa761","article-title":"Efficacy of a Dengue Vaccine Candidate (TAK-003) in Healthy Children and Adolescents 2 Years after Vaccination","volume":"225","author":"Biswal","year":"2022","journal-title":"J. Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0065-3527(03)59002-9","article-title":"Molecular Biology of Flaviviruses","volume":"59","author":"Lindenbach","year":"2003","journal-title":"Adv. Virus Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.antiviral.2015.03.014","article-title":"The Flavivirus NS2B\u2013NS3 Protease\u2013Helicase as a Target for Antiviral Drug Development","volume":"118","author":"Luo","year":"2015","journal-title":"Antivir. Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Starvaggi, J., Previti, S., Zappal\u00e0, M., and Ettari, R. (2024). The Inhibition of NS2B\/NS3 Protease: A New Therapeutic Opportunity to Treat Dengue and Zika Virus Infection. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25084376"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1039\/D0MD00154F","article-title":"Covalent Inhibitors: A Rational Approach to Drug Discovery","volume":"11","author":"Sutanto","year":"2020","journal-title":"RSC Med. Chem."},{"key":"ref_31","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_32","unstructured":"Knyazhanskaya, E., Morais, M.C., and Choi, K.H. (2021). Flavivirus Enzymes and Their Inhibitors. The Enzymes, Academic Press."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Agback, P., Woestenenk, E., and Agback, T. (2020). Probing Contacts of Inhibitor Locked in Transition States in the Catalytic Triad of DENV2 Type Serine Protease and Its Mutants by 1H, 19F and 15\u2009N NMR Spectroscopy. BMC Mol. Cell Biol., 21.","DOI":"10.1186\/s12860-020-00283-0"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1021\/acs.jmedchem.6b01021","article-title":"Peptide\u2013Boronic Acid Inhibitors of Flaviviral Proteases: Medicinal Chemistry and Structural Biology","volume":"60","author":"Nitsche","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_35","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_36","doi-asserted-by":"crossref","first-page":"e202200336","DOI":"10.1002\/cmdc.202200336","article-title":"Boroleucine-Derived Covalent Inhibitors of the ZIKV Protease","volume":"18","author":"Braun","year":"2023","journal-title":"ChemMedChem"},{"key":"ref_37","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_38","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\u2013NS3 Protease","volume":"92","author":"Yin","year":"2011","journal-title":"Antivir. Res."},{"key":"ref_39","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_40","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_41","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_42","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1021\/acs.biochem.7b01127","article-title":"Inhibitor Bound Dengue NS2B-NS3pro Reveals Multiple Dynamic Binding Modes","volume":"57","author":"Gibbs","year":"2018","journal-title":"Biochemistry"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4067","DOI":"10.1016\/j.bmc.2011.05.015","article-title":"Synthesis and Biological Evaluation of \u03b1-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_44","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.bbrc.2022.08.060","article-title":"Discovery of Highly Potent DENV NS2B-NS3 Covalent Inhibitors Containing a Phenoxymethylphenyl Residue","volume":"627","author":"Cheng","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Brecher, M., Li, Z., Liu, B., Zhang, J., Koetzner, C.A., Alifarag, A., Jones, S.A., Lin, Q., Kramer, L.D., and Li, H. (2017). A Conformational Switch High-Throughput Screening Assay and Allosteric Inhibition of the Flavivirus NS2B-NS3 Protease. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006411"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"107914","DOI":"10.1016\/j.bioorg.2024.107914","article-title":"Advances in Drug Discovery of Flavivirus NS2B-NS3pro Serine Protease Inhibitors for the Treatment of Dengue, Zika, and West Nile Viruses","volume":"153","author":"Lopes","year":"2024","journal-title":"Bioorg. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1021\/acsinfecdis.3c00330","article-title":"A Non-Active-Site Inhibitor with Selectivity for Zika Virus NS2B-NS3 Protease","volume":"10","author":"Cruz","year":"2024","journal-title":"ACS Infect. Dis."},{"key":"ref_48","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_49","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s10930-020-09884-2","article-title":"Covalent Versus Non-Covalent Enzyme Inhibition: Which Route Should We Take? A Justification of the Good and Bad from Molecular Modelling Perspective","volume":"39","author":"Aljoundi","year":"2020","journal-title":"Protein J."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Grabski, H., Grabska, S., and Abagyan, R. (2024). Identifying Allosteric Small-Molecule Binding Sites of Inactive NS2B-NS3 Proteases of Pathogenic Flaviviridae. Viruses, 17.","DOI":"10.3390\/v17010006"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"25677","DOI":"10.1021\/acsomega.0c00039","article-title":"Curcumin Allosterically Inhibits the Dengue NS2B-NS3 Protease by Disrupting Its Active Conformation","volume":"5","author":"Lim","year":"2020","journal-title":"ACS Omega"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2798","DOI":"10.1021\/acsomega.1c05569","article-title":"Myricetin Allosterically Inhibits the Dengue NS2B-NS3 Protease by Disrupting the Active and Locking the Inactive Conformations","volume":"7","author":"Dang","year":"2022","journal-title":"ACS Omega"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Roy, A., Lim, L., Srivastava, S., Lu, Y., and Song, J. (2017). Solution Conformations of Zika NS2B-NS3pro and Its Inhibition by Natural Products from Edible Plants. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0180632"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.bmc.2014.12.015","article-title":"Flavonoids as Noncompetitive Inhibitors of Dengue Virus NS2B-NS3 Protease: Inhibition Kinetics and Docking Studies","volume":"23","author":"Wu","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Eberle, R.J., Olivier, D.S., Pacca, C.C., Avilla, C.M.S., Nogueira, M.L., Amaral, M.S., Willbold, D., Arni, R.K., and Coronado, M.A. (2021). In Vitro Study of Hesperetin and Hesperidin as Inhibitors of Zika and Chikungunya Virus Proteases. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0246319"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"16348","DOI":"10.1038\/s41598-019-52626-3","article-title":"The Citrus Flavonoid Naringenin Impairs the In Vitro Infection of Human Cells by Zika Virus","volume":"9","author":"Cataneo","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"132855","DOI":"10.1016\/j.ijbiomac.2024.132855","article-title":"Identification of Novel and Potential Inhibitors against the Dengue Virus NS2B\/NS3 Protease Using Virtual Screening and Biomolecular Simulations","volume":"272","author":"Nasir","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"106269","DOI":"10.1016\/j.bioorg.2022.106269","article-title":"Allosteric Quinoxaline-Based Inhibitors of the Flavivirus NS2B\/NS3 Protease","volume":"131","author":"Zephyr","year":"2023","journal-title":"Bioorg. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"7759","DOI":"10.1080\/07391102.2024.2335296","article-title":"Discovery of Azaleatin as a Potential Allosteric Inhibitor for Dengue NS2B-NS3 Protease Using In Vitro and In Silico Studies","volume":"43","author":"Mustafa","year":"2025","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Mahalapbutr, P., Hengphasatporn, K., Manimont, W., Vajarintarangoon, L., Shigeta, Y., Bhat, N., Aiebchun, T., Nutho, B., Hannongbua, S., and Rungrotmongkol, T. (2025). Identification of Sulfonamide-Vinyl Sulfone\/Chalcone and Berberine-Cinnamic Acid Hybrids as Potent DENV and ZIKV NS2B\/NS3 Allosteric Inhibitors. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262311762"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"113767","DOI":"10.1016\/j.ejmech.2021.113767","article-title":"Synthesis, Structure-Activity Relationship and Antiviral Activity of Indole-Containing Inhibitors of Flavivirus NS2B-NS3 Protease","volume":"225","author":"Nie","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Paulis, A., and Tramontano, E. (2023). Unlocking STING as a Therapeutic Antiviral Strategy. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087448"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3414","DOI":"10.1021\/acs.chemrev.1c00716","article-title":"Therapeutic Interventions Targeting Innate Immune Receptors: A Balancing Act","volume":"122","author":"Cao","year":"2022","journal-title":"Chem. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1056\/NEJMra2206346","article-title":"Humoral Innate Immunity and Acute-Phase Proteins","volume":"388","author":"Mantovani","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.autrev.2018.10.005","article-title":"Innate Immune-Responses and Their Role in Driving Autoimmunity","volume":"18","author":"Toubi","year":"2019","journal-title":"Autoimmun. Rev."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1111\/1348-0421.12669","article-title":"Cytosolic DNA-Sensing Immune Response and Viral Infection","volume":"63","author":"Abe","year":"2019","journal-title":"Microbiol. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Wicherska-Paw\u0142owska, K., Wr\u00f3bel, T., and Rybka, J. (2021). Toll-Like Receptors (TLRs), NOD-Like Receptors (NLRs), and RIG-I-Like Receptors (RLRs) in Innate Immunity. TLRs, NLRs, and RLRs Ligands as Immunotherapeutic Agents for Hematopoietic Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413397"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/s41392-021-00687-0","article-title":"Pattern Recognition Receptors in Health and Diseases","volume":"6","author":"Li","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_69","first-page":"199","article-title":"Innate Immune Response to Viral Infection","volume":"43","author":"Beirag","year":"2025","journal-title":"Cytokine"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Sekaran, S.D., Ismail, A.A., Thergarajan, G., Chandramathi, S., Rahman, S.K.H., Mani, R.R., Jusof, F.F., Lim, Y.A.L., and Manikam, R. (2022). Host Immune Response against DENV and ZIKV Infections. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.975222"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"341","DOI":"10.4269\/ajtmh.2012.11-0469","article-title":"A Three-Component Biomarker Panel for Prediction of Dengue Hemorrhagic Fever","volume":"86","author":"Brasier","year":"2012","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1089\/vim.2019.0082","article-title":"Immune Evasion Strategies Used by Zika Virus to Infect the Fetal Eye and Brain","volume":"33","author":"Nelson","year":"2020","journal-title":"Viral Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1016\/j.immuni.2024.02.019","article-title":"New Frontiers in the CGAS-STING Intracellular DNA-Sensing Pathway","volume":"57","author":"Dvorkin","year":"2024","journal-title":"Immunity"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1038\/nsmb.2331","article-title":"Structure of STING Bound to Cyclic Di-GMP Reveals the Mechanism of Cyclic Dinucleotide Recognition by the Immune System","volume":"19","author":"Shu","year":"2012","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/nri1604","article-title":"Mechanisms of Type-I- and Type-II-Interferon-Mediated Signalling","volume":"5","author":"Platanias","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/s41586-019-1000-2","article-title":"Structural Basis of STING Binding with and Phosphorylation by TBK1","volume":"567","author":"Zhang","year":"2019","journal-title":"Nature"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jaut.2017.03.008","article-title":"Regulation of Type I Interferon Signaling in Immunity and Inflammation: A Comprehensive Review","volume":"83","author":"Chen","year":"2017","journal-title":"J. Autoimmun."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.immuni.2019.03.025","article-title":"Shared and Distinct Functions of Type I and Type III Interferons","volume":"50","author":"Lazear","year":"2019","journal-title":"Immunity"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"15623","DOI":"10.1073\/pnas.95.26.15623","article-title":"Identification of Genes Differentially Regulated by Interferon \u03b1, \u03b2, or \u03b3 Using Oligonucleotide Arrays","volume":"95","author":"Der","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/nri2314","article-title":"Interferon-Inducible Antiviral Effectors","volume":"8","author":"Sadler","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.cytogfr.2014.07.015","article-title":"Interferons: Success in Anti-Viral Immunotherapy","volume":"25","author":"Lin","year":"2014","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.3390\/ph3041162","article-title":"Safety, Tolerability, and Immunogenicity of Interferons","volume":"3","author":"Tovey","year":"2010","journal-title":"Pharmaceuticals"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1358\/dnp.2008.21.2.1188193","article-title":"The Antiviral Activity of Toll-Like Receptor 7 and 7\/8 Agonists","volume":"21","author":"Miller","year":"2008","journal-title":"Drug News Perspect."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1067\/mai.2003.102","article-title":"The Novel Synthetic Immune Response Modifier R-848 (Resiquimod) Shifts Human Allergen-Specific CD4+ TH2 Lymphocytes into IFN-\u03b3\u2013Producing Cells","volume":"111","author":"Brugnolo","year":"2003","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1006\/cimm.1998.1406","article-title":"Modulation of TH1 and TH2 Cytokine Production with the Immune Response Modifiers, R-848 and Imiquimod","volume":"191","author":"Wagner","year":"1999","journal-title":"Cell. Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.virol.2018.07.014","article-title":"Toll-Like Receptor Agonist R848 Blocks Zika Virus Replication by Inducing the Antiviral Protein Viperin","volume":"522","author":"Vanwalscappel","year":"2018","journal-title":"Virology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.micinf.2011.11.015","article-title":"Viperin, a Key Player in the Antiviral Response","volume":"14","author":"Mattijssen","year":"2012","journal-title":"Microbes Infect."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Sariol, C.A., Mart\u00ednez, M.I., Rivera, F., Rodr\u00edguez, I.V., Pantoja, P., Abel, K., Arana, T., Giavedoni, L., Hodara, V., and White, L.J. (2011). Decreased Dengue Replication and an Increased Anti-Viral Humoral Response with the Use of Combined Toll-Like Receptor 3 and 7\/8 Agonists in Macaques. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019323"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Liang, Z., Wu, S., Li, Y., He, L., Wu, M., Jiang, L., Feng, L., Zhang, P., and Huang, X. (2011). Activation of Toll-Like Receptor 3 Impairs the Dengue Virus Serotype 2 Replication through Induction of IFN-\u03b2 in Cultured Hepatoma Cells. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023346"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"4180","DOI":"10.1128\/JVI.03114-13","article-title":"Inhibition of Dengue and Chikungunya Virus Infections by RIG-I-Mediated Type I Interferon-Independent Stimulation of the Innate Antiviral Response","volume":"88","author":"Olagnier","year":"2014","journal-title":"J. Virol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e00102-19","DOI":"10.1128\/JVI.00102-19","article-title":"RIG-I Activation by a Designer Short RNA Ligand Protects Human Immune Cells against Dengue Virus Infection Without Causing Cytotoxicity","volume":"93","author":"Ho","year":"2019","journal-title":"J. Virol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"8011","DOI":"10.1128\/JVI.00845-15","article-title":"Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists","volume":"89","author":"Chiang","year":"2015","journal-title":"J. Virol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.antiviral.2017.10.001","article-title":"A Cell-Based High Throughput Screening Assay for the Discovery of CGAS-STING Pathway Agonists","volume":"147","author":"Liu","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"101024","DOI":"10.1016\/j.xcrm.2023.101024","article-title":"Innate Immune Pathway Modulator Screen Identifies STING Pathway Activation as a Strategy to Inhibit Multiple Families of Arbo and Respiratory Viruses","volume":"4","author":"Garcia","year":"2023","journal-title":"Cell Rep. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1128\/JVI.02202-15","article-title":"Targeting Innate Immunity for Antiviral Therapy Through Small Molecule Agonists of the RLR Pathway","volume":"90","author":"Pattabhi","year":"2016","journal-title":"J. Virol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e00452-17","DOI":"10.1128\/mBio.00452-17","article-title":"A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses","volume":"8","author":"Pryke","year":"2017","journal-title":"mBio"},{"key":"ref_97","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. Adv."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Damen, M., Izidoro, M., Okamoto, D., Oliveira, L., Amatdjais-Groenen, H., van Dongen, S., van Cleef, K., van Rij, R., Dieteren, C., and Giron\u00e9s, D. (2022). Cationic Geminoid Peptide Amphiphiles Inhibit DENV2 Protease, Furin, and Viral Replication. Molecules, 27.","DOI":"10.3390\/molecules27103217"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"16708","DOI":"10.1002\/chem.201202276","article-title":"Multivalent Design of Apoptosis-Inducing Bid-BH3 Peptide\u2013Oligosaccharides Boosts the Intracellular Activity at Identical Overall Peptide Concentrations","volume":"18","author":"Richter","year":"2012","journal-title":"Chem.\u2014A Eur. J."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"837","DOI":"10.3762\/bjoc.11.93","article-title":"Peptide\u2013Polymer Ligands for a Tandem WW-Domain, an Adaptive Multivalent Protein\u2013Protein Interaction: Lessons on the Thermodynamic Fitness of Flexible Ligands","volume":"11","author":"Koschek","year":"2015","journal-title":"Beilstein J. Org. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1021\/acsmedchemlett.1c00515","article-title":"Nanoparticular Inhibitors of Flavivirus Proteases from Zika, West Nile and Dengue Virus Are Cell-Permeable Antivirals","volume":"12","author":"Schroeder","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1007\/s00106-007-1573-1","article-title":"Plattenepithelkarzinome Im Kopf-Hals-Bereich","volume":"56","author":"Lorenz","year":"2008","journal-title":"HNO"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.cellsig.2017.04.001","article-title":"Niclosamide: Beyond an Antihelminthic Drug","volume":"41","author":"Chen","year":"2018","journal-title":"Cell. Signal."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1038\/cr.2017.88","article-title":"Existing Drugs as Broad-Spectrum and Potent Inhibitors for Zika Virus by Targeting NS2B-NS3 Interaction","volume":"27","author":"Li","year":"2017","journal-title":"Cell Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e2300292","DOI":"10.1002\/ardp.202300292","article-title":"Repurposing of Investigational Cancer Drugs: Early Phase Discovery of Dengue Virus NS2B\/NS3 Protease Inhibitors","volume":"356","author":"Saleem","year":"2023","journal-title":"Arch. Pharm."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1038\/aps.2015.56","article-title":"Policresulen, a Novel NS2B\/NS3 Protease Inhibitor, Effectively Inhibits the Replication of DENV2 Virus in BHK-21 Cells","volume":"36","author":"Wu","year":"2015","journal-title":"Acta Pharmacol. Sin."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/2\/232\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T16:04:56Z","timestamp":1771517096000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/2\/232"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,19]]},"references-count":106,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["pathogens15020232"],"URL":"https:\/\/doi.org\/10.3390\/pathogens15020232","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,19]]}}}