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HIV-1 Integrase Strand Transfer Inhibitors with Reduced Susceptibility to Drug Resistant Mutant Integrases

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Title: HIV-1 Integrase Strand Transfer Inhibitors with Reduced Susceptibility to Drug Resistant Mutant Integrases
Authors: Zhao, XZ
Smith, SJ
Maskell, DP
Metifiot, M
Pye, VE
Fesen, K
Marchand, C
Pommier, Y
Cherepanov, P
Hughes, SH
Burke, TR
Item Type: Journal Article
Abstract: HIV integrase (IN) strand transfer inhibitors (INSTIs) are among the newest anti-AIDS drugs; however, mutant forms of IN can confer resistance. We developed noncytotoxic naphthyridine-containing INSTIs that retain low nanomolar IC50 values against HIV-1 variants harboring all of the major INSTI-resistant mutations. We found by analyzing crystal structures of inhibitors bound to the IN from the prototype foamy virus (PFV) that the most successful inhibitors show striking mimicry of the bound viral DNA prior to 3′-processing and the bound host DNA prior to strand transfer. Using this concept of “bi-substrate mimicry,” we developed a new broadly effective inhibitor that not only mimics aspects of both the bound target and viral DNA but also more completely fills the space they would normally occupy. Maximizing shape complementarity and recapitulating structural components encompassing both of the IN DNA substrates could serve as a guiding principle for the development of new INSTIs.
Issue Date: 25-Jan-2016
Date of Acceptance: 25-Jan-2016
URI: http://hdl.handle.net/10044/1/50369
DOI: https://dx.doi.org/10.1021/acschembio.5b00948
ISSN: 1554-8937
Publisher: American Chemical Society
Start Page: 1074
End Page: 1081
Journal / Book Title: ACS Chemical Biology
Volume: 11
Issue: 4
Copyright Statement: This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
CROSS-RESISTANCE
RALTEGRAVIR
DOLUTEGRAVIR
ELVITEGRAVIR
DERIVATIVES
MECHANISMS
MUTATIONS
EVOLUTION
INFECTION
FREQUENCY
Crystallography, X-Ray
Drug Resistance, Viral
HIV Integrase
HIV Integrase Inhibitors
HIV Integrase
HIV Integrase Inhibitors
Crystallography, X-Ray
Drug Resistance, Viral
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
CROSS-RESISTANCE
RALTEGRAVIR
DOLUTEGRAVIR
ELVITEGRAVIR
DERIVATIVES
MECHANISMS
MUTATIONS
EVOLUTION
INFECTION
FREQUENCY
03 Chemical Sciences
06 Biological Sciences
Organic Chemistry
Publication Status: Published
Open Access location: http://pubs.acs.org/doi/pdf/10.1021/acschembio.5b00948
Appears in Collections:Department of Medicine



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