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HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants

2008Journal article Open access
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dc.contributor.authorAltman, Michael D.
dc.contributor.authorAli, Akbar
dc.contributor.authorKumar Reddy, G. S. Kiran
dc.contributor.authorNalam, Madhavi N. L.
dc.contributor.authorAnjum, Saima Ghafoor
dc.contributor.authorCao, Hong
dc.contributor.authorChellappan, Sripriya
dc.contributor.authorKairys, Visvaldas
dc.contributor.authorFernandes, Miguel X.
dc.contributor.authorGilson, Michael K.
dc.contributor.authorSchiffer, Celia A.
dc.contributor.authorRana, Tariq M.
dc.contributor.authorTidor, Bruce
dc.date.accessioned2023-02-07T11:46:53Z
dc.date.available2023-02-07T11:46:53Z
dc.date.issued2008
dc.description.abstractThe acquisition of drug-resistant mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a general strategy, inverse design using the substrate envelope, to develop inhibitors of HIV-1 protease. Structure-based computation was used to design inhibitors predicted to stay within a consensus substrate volume in the binding site. Two rounds of design, synthesis, experimental testing, and structural analysis were carried out, resulting in a total of 51 compounds. Improvements in design methodology led to a roughly 1000-fold affinity enhancement to a wild-type protease for the best binders, from a Ki of 30–50 nM in round one to below 100 pM in round two. Crystal structures of a subset of complexes revealed a binding mode similar to each design that respected the substrate envelope in nearly all cases. All four best binders from round one exhibited broad specificity against a clinically relevant panel of drug-resistant HIV-1 protease variants, losing no more than 6–13-fold affinity relative to wild type. Testing a subset of second-round compounds against the panel of resistant variants revealed three classes of inhibitors: robust binders (maximum affinity loss of 14–16-fold), moderate binders (35–80-fold), and susceptible binders (greater than 100-fold). Although for especially high-affinity inhibitors additional factors may also be important, overall, these results suggest that designing inhibitors using the substrate envelope may be a useful strategy in the development of therapeutics with low susceptibility to resistance.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationAltman, M. D., Ali, A., Kumar Reddy, G. K., Nalam, M. N., Anjum, S. G., Cao, H., ... & Tidor, B. (2008). HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants. Journal of the American Chemical Society, 130(19), 6099-6113.pt_PT
dc.identifier.doi10.1021/ja076558ppt_PT
dc.identifier.urihttp://hdl.handle.net/10400.13/5008
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Chemical Societypt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectHIV-1pt_PT
dc.subjectChemical structurept_PT
dc.subjectCrystal structurept_PT
dc.subjectGeneticspt_PT
dc.subjectInhibitorspt_PT
dc.subjectPeptides and proteinspt_PT
dc.subject.pt_PT
dc.subjectFaculdade de Ciências Exatas e da Engenhariapt_PT
dc.titleHIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variantspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage6113pt_PT
oaire.citation.issue19pt_PT
oaire.citation.startPage6099pt_PT
oaire.citation.titleJournal of the American Chemical Societypt_PT
oaire.citation.volume130pt_PT
person.familyNameKairys
person.familyNameFernandes
person.givenNameVisvaldas
person.givenNameMiguel Xavier
person.identifierK-9893-2013
person.identifier.ciencia-idA716-F916-AFB2
person.identifier.ciencia-idED1D-3C7A-467C
person.identifier.orcid0000-0002-5427-0175
person.identifier.orcid0000-0002-1840-616X
person.identifier.ridA-4373-2013
person.identifier.scopus-author-id6602925161
person.identifier.scopus-author-id35466972500
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication43821a45-10cf-4dbd-bc5a-fa88d146fc36
relation.isAuthorOfPublication8dab9a0d-f44a-4d2d-b9b1-7b3145162ca3
relation.isAuthorOfPublication.latestForDiscovery8dab9a0d-f44a-4d2d-b9b1-7b3145162ca3

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