- Covalent Inhibition of Wild-Type HIV-1 Reverse Transcriptase Using a Fluorosulfate Warhead
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Covalent inhibitors of wild-type HIV-1 reverse transcriptase (CRTIs) are reported. Three compounds derived from catechol diether non-nucleoside inhibitors (NNRTIs) with addition of a fluorosulfate warhead are demonstrated to covalently modify Tyr181 of HIV-RT. X-ray crystal structures for complexes of the CRTIs with the enzyme are provided, which fully demonstrate the covalent attachment, and confirmation is provided by appropriate mass shifts in ESI-TOF mass spectra. The three CRTIs and six noncovalent analogues are found to be potent inhibitors with both IC50 values for in vitro inhibition of WT RT and EC50 values for cytopathic protection of HIV-1-infected human T-cells in the 5-320 nM range.
- Ippolito, Joseph A.,Niu, Haichan,Bertoletti, Nicole,Carter, Zachary J.,Jin, Shengyan,Spasov, Krasimir A.,Cisneros, José A.,Valhondo, Margarita,Cutrona, Kara J.,Anderson, Karen S.,Jorgensen, William L.
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p. 249 - 255
(2021/01/26)
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- Discovery of 3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2- chlorophenoxy}-5-chlorobenzonitrile (MK-4965): A potent, orally bioavailable HIV-1 non-nucleoside reverse transcriptase inhibitor with improved potency against key mutant viruses
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Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of standard combination antiviral therapies producing clinical outcomes with
- Tucker, Thomas J.,Sisko, John T.,Tynebor, Robert M.,Williams, Theresa M.,Felock, Peter J.,Flynn, Jessica A.,Lai, Ming-Tain,Liang, Yuexia,McGaughey, Georgia,Liu, Meiquing,Miller, Mike,Moyer, Gregory,Munshi, Vandna,Perlow-Poehnelt, Rebecca,Prasad, Sridhar,Reid, John C.,Sanchez, Rosa,Torrent, Maricel,Vacca, Joseph P.,Wan, Bang-Lin,Yan, Youwei
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experimental part
p. 6503 - 6511
(2009/10/17)
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- The design and synthesis of diaryl ether second generation HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with enhanced potency versus key clinical mutations
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Using a combination of traditional Medicinal Chemistry/SAR analysis, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad antiviral activity against a number of key clinical mutations.
- Tucker, Thomas J.,Saggar, Sandeep,Sisko, John T.,Tynebor, Robert M.,Williams, Theresa M.,Felock, Peter J.,Flynn, Jessica A.,Lai, Ming-Tain,Liang, Yuexia,McGaughey, Georgia,Liu, Meiquing,Miller, Mike,Moyer, Gregory,Munshi, Vandna,Perlow-Poehnelt, Rebecca,Prasad, Sridhar,Sanchez, Rosa,Torrent, Maricel,Vacca, Joseph P.,Wan, Bang-Lin,Yan, Youwei
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p. 2959 - 2966
(2008/12/23)
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- HIV reverse transcriptase inhibitors
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Compounds having the structure: are HIV reverse transcriptase inhibitors, wherein A, X, Y, Z, R1 and R2 are defined herein. The compounds and their pharmaceutically acceptable salts are useful in the inhibition of HIV reverse transcriptase, the prophylaxis and treatment of infection by HIV and in the prophylaxis, delay in the onset, and treatment of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.
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Page/Page column 34
(2010/11/25)
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