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dc.contributor.author
Lee, Won Gil
dc.contributor.author
Gallardo Macias, Ricardo
dc.contributor.author
Frey, Kathleen M
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Spasov, Krasimir A.
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Bollini, Mariela
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dc.contributor.author
Anderson, Karen S.
dc.contributor.author
Jorgensen, William L.
dc.date.available
2017-10-11T19:24:10Z
dc.date.issued
2013-10
dc.identifier.citation
Lee, Won Gil; Gallardo Macias, Ricardo; Frey, Kathleen M; Spasov, Krasimir A.; Bollini, Mariela; et al.; Paste one version of a text here.picomolar inhibitors of HIV reverse transcriptase featuring bicyclic replacement of a cyanovinylphenyl group; American Chemical Society; Journal of the American Chemical Society; 135; 44; 10-2013; 16705-16713
dc.identifier.issn
0002-7863
dc.identifier.uri
http://hdl.handle.net/11336/26444
dc.description.abstract
Members of the catechol diether class are highly potent non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). The most active compounds yield EC50 values below 0.5 nM in assays using human T-cells infected by wild-type HIV-1. However, these compounds such as rilpivirine, the most recently FDA-approved NNRTI, bear a cyanovinylphenyl (CVP) group. This is an uncommon substructure in drugs that gives reactivity concerns. In the present work, computer simulations were used to design bicyclic replacements for the CVP group. The predicted viability of a 2-cyanoindolizinyl alternative was confirmed experimentally and provided compounds with 0.4 nM activity against the wild-type virus. The compounds also performed well with EC50 values of 10 nM against the challenging HIV-1 variant that contains the Lys103Asn/Tyr181Cys double mutation in the RT enzyme. Indolyl and benzofuranyl analogues were also investigated; the most potent compounds in these cases have EC50 values toward wild-type HIV-1 near 10 nM and high-nanomolar activities toward the double-variant. The structural expectations from the modeling were much enhanced by obtaining an X-ray crystal structure at 2.88 Å resolution for the complex of the parent 2-cyanoindolizine 10b and HIV-1 RT. The aqueous solubilities of the most potent indolizine analogues were also measured to be ∼40 μg/mL, which is similar to that for the approved drug efavirenz and ∼1000-fold greater than for rilpivirine.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Chemical Society
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Picomolar Inhibitors
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Hiv-Rt
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Otras Ciencias Químicas
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Ciencias Químicas
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CIENCIAS NATURALES Y EXACTAS
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dc.title
Paste one version of a text here.picomolar inhibitors of HIV reverse transcriptase featuring bicyclic replacement of a cyanovinylphenyl group
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2017-09-28T18:11:19Z
dc.journal.volume
135
dc.journal.number
44
dc.journal.pagination
16705-16713
dc.journal.pais
Estados Unidos
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dc.journal.ciudad
Washington D. C.
dc.description.fil
Fil: Lee, Won Gil. University of Yale; Estados Unidos
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Fil: Gallardo Macias, Ricardo. University of Yale; Estados Unidos
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Fil: Frey, Kathleen M. University of Yale; Estados Unidos
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Fil: Spasov, Krasimir A.. University of Yale; Estados Unidos
dc.description.fil
Fil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Anderson, Karen S.. University of Yale; Estados Unidos
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Fil: Jorgensen, William L.. University of Yale; Estados Unidos
dc.journal.title
Journal of the American Chemical Society
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/abs/10.1021/ja408917n
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1021/ja408917n
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