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dc.contributor.authorChang, Kyeong-Ok
dc.contributor.authorKim, Yunjeong
dc.contributor.authorLovell, Scott
dc.contributor.authorRathnayake, Athri D.
dc.contributor.authorGroutas, William C.
dc.date.accessioned2019-04-10T21:24:31Z
dc.date.available2019-04-10T21:24:31Z
dc.date.issued2019-02-25
dc.identifier.citationChang, K.-O.; Kim, Y.; Lovell, S.; Rathnayake, A.D.; Groutas, W.C. Antiviral Drug Discovery: Norovirus Proteases and Development of Inhibitors. Viruses 2019, 11, 197en_US
dc.identifier.issn1999-4915
dc.identifier.otherWOS:000460803200107
dc.identifier.urihttps://doi.org/10.3390/v11020197
dc.identifier.urihttp://hdl.handle.net/10057/16005
dc.descriptionThis is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).en_US
dc.description.abstractProteases are a major enzyme group playing important roles in a wide variety of biological processes in life forms ranging from viruses to mammalians. The aberrant activity of proteases can lead to various diseases; consequently, host proteases have been the focus of intense investigation as potential therapeutic targets. A wide range of viruses encode proteases which play an essential role in viral replication and, therefore, constitute attractive targets for the development of antiviral therapeutics. There are numerous examples of successful drug development targeting cellular and viral proteases, including antivirals against human immunodeficiency virus and hepatitis C virus. Most FDA-approved antiviral agents are peptidomimetics and macrocyclic compounds that interact with the active site of a targeted protease. Norovirus proteases are cysteine proteases that contain a chymotrypsin-like fold in their 3D structures. This review focuses on our group's efforts related to the development of norovirus protease inhibitors as potential anti-norovirus therapeutics. These protease inhibitors are rationally designed transition-state inhibitors encompassing dipeptidyl, tripeptidyl and macrocyclic compounds. Highly effective inhibitors validated in X-ray co-crystallization, enzyme and cell-based assays, as well as an animal model, were generated by launching an optimization campaign utilizing the initial hit compounds. A prodrug approach was also explored to improve the pharmacokinetics (PK) of the identified inhibitors.en_US
dc.description.sponsorshipNational Institutes of Health Grants AI109039 and AI130092.en_US
dc.language.isoen_USen_US
dc.publisherMDPI AG, Basel, Switzerlanden_US
dc.relation.ispartofseriesViruses;v.11:no.2
dc.subjectNorovirusesen_US
dc.subject3C-like proteaseen_US
dc.subjectProtease inhibitorsen_US
dc.subjectAntiviral drug developmenten_US
dc.titleAntiviral drug discovery: norovirus proteases and development of inhibitorsen_US
dc.typeArticleen_US
dc.rights.holder© 1996-2019 MDPen_US


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