Catching a Moving Target: Comparative Modeling of Flaviviral NS2B-NS3 Reveals Small Molecule Zika Protease Inhibitors
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Pach, Szymon; Sarter, Tim M; Yousef, Rafe; Schaller, David; Bergemann, Silke; Arkona, Christoph; Rademann, Jörg; Nitsche, Christoph; Wolber, Gerhard
Description
The pivotal role of viral proteases in virus replication has already been successfully exploited in several antiviral drug design campaigns. However, no efficient antivirals are currently available against flaviviral infections. In this study, we present lead-like small molecule inhibitors of the Zika Virus (ZIKV) NS2B-NS3 protease. Since only few nonpeptide competitive ligands are known, we take advantage of the high structural similarity with the West Nile Virus (WNV) NS2B-NS3 protease. A...[Show more]
dc.contributor.author | Pach, Szymon | |
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dc.contributor.author | Sarter, Tim M | |
dc.contributor.author | Yousef, Rafe | |
dc.contributor.author | Schaller, David | |
dc.contributor.author | Bergemann, Silke | |
dc.contributor.author | Arkona, Christoph | |
dc.contributor.author | Rademann, Jörg | |
dc.contributor.author | Nitsche, Christoph | |
dc.contributor.author | Wolber, Gerhard | |
dc.date.accessioned | 2022-06-27T03:03:39Z | |
dc.date.available | 2022-06-27T03:03:39Z | |
dc.identifier.issn | 1948-5875 | |
dc.identifier.uri | http://hdl.handle.net/1885/268509 | |
dc.description.abstract | The pivotal role of viral proteases in virus replication has already been successfully exploited in several antiviral drug design campaigns. However, no efficient antivirals are currently available against flaviviral infections. In this study, we present lead-like small molecule inhibitors of the Zika Virus (ZIKV) NS2B-NS3 protease. Since only few nonpeptide competitive ligands are known, we take advantage of the high structural similarity with the West Nile Virus (WNV) NS2B-NS3 protease. A comparative modeling approach involving our in-house software PyRod was employed to systematically analyze the binding sites and develop molecular dynamics-based 3D pharmacophores for virtual screening. The identified compounds were biochemically characterized revealing low micromolar affinity for both ZIKV and WNV proteases. Their lead-like properties together with rationalized binding modes represent valuable starting points for future lead optimization. Since the NS2B-NS3 protease is highly conserved among flaviviruses, these compounds may also drive the development of pan-flaviviral antiviral drugs. | |
dc.description.sponsorship | C.N. thanks the Australian Research Council for a Discovery Early Career Research Award (DE190100015). | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en_AU | |
dc.publisher | American Chemical Society | |
dc.rights | © 2020 American Chemical Society | |
dc.source | ACS medicinal chemistry letters | |
dc.subject | Flavivirus | |
dc.subject | protease | |
dc.subject | inhibitors | |
dc.subject | PyRod | |
dc.subject | 3D pharmacophores | |
dc.subject | Dynophores | |
dc.title | Catching a Moving Target: Comparative Modeling of Flaviviral NS2B-NS3 Reveals Small Molecule Zika Protease Inhibitors | |
dc.type | Journal article | |
local.identifier.citationvolume | 11 | |
dcterms.dateAccepted | 2020 | |
dc.date.issued | 2020-04-09 | |
local.identifier.ariespublication | a383154xPUB11455 | |
local.publisher.url | http://pubs.acs.org/journal/amclct | |
local.type.status | Accepted Version | |
local.contributor.affiliation | Nitsche, Christoph, Research School of Chemistry, The Australian National University | |
dc.relation | http://purl.org/au-research/grants/arc/DE190100015 | |
local.bibliographicCitation.issue | 4 | |
local.bibliographicCitation.startpage | 514 | |
local.bibliographicCitation.lastpage | 520 | |
local.identifier.doi | 10.1021/acsmedchemlett.9b00629 | |
dcterms.accessRights | Open Access | |
dc.provenance | https://v2.sherpa.ac.uk/id/publication/7764..."The Accepted Version can be archived in a Non-Commercial Institutional Repository If Required by Funder, If Required by Institution. 12 months embargo." from SHERPA/RoMEO site (as at 27/06/2022). This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS medicinal chemistry letters, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://dx.doi.org/10.1021/10.1021/acsmedchemlett.9b00629 | |
Collections | ANU Research Publications |
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File | Description | Size | Format | Image |
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Manuscript_ACSMedChemLett2020.pdf | Main article | 4.17 MB | Adobe PDF |
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