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| '''Crystal structure of HIV-1 reverse transcriptase (RT) in complex with JANSSEN-R165481'''
| | ===Crystal structure of HIV-1 reverse transcriptase (RT) in complex with JANSSEN-R165481=== |
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| ==Overview==
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| In the treatment of AIDS, the efficacy of all drugs, including non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT), has been limited by the rapid appearance of drug-resistant viruses. Lys103Asn, Tyr181Cys, and Tyr188Leu are some of the most common RT mutations that cause resistance to NNRTIs in the clinic. We report X-ray crystal structures for RT complexed with three different pyridinone derivatives, R157208, R165481, and R221239, at 2.95, 2.9, and 2.43 A resolution, respectively. All three ligands exhibit nanomolar or subnanomolar inhibitory activity against wild-type RT, but varying activities against drug-resistant mutants. R165481 and R221239 differ from most NNRTIs in that binding does not involve significant contacts with Tyr181. These compounds strongly inhibit wild-type HIV-1 RT and drug-resistant variants, including Tyr181Cys and Lys103Asn RT. These properties result in part from an iodine atom on the pyridinone ring of both inhibitors that interacts with the main-chain carbonyl oxygen of Tyr188. An acrylonitrile substituent on R165481 substantially improves the activity of the compound against wild-type RT (and several mutants) and provides a way to generate novel inhibitors that could interact with conserved elements of HIV-1 RT at the polymerase catalytic site. In R221239, there is a flexible linker to a furan ring that permits interactions with Val106, Phe227, and Pro236. These contacts appear to enhance the inhibitory activity of R221239 against the HIV-1 strains that carry the Val106Ala, Tyr188Leu, and Phe227Cys mutations.
| | The line below this paragraph, {{ABSTRACT_PUBMED_16302798}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 16302798 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_16302798}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Reverse transcriptase]] | | [[Category: Reverse transcriptase]] |
| [[Category: Rt]] | | [[Category: Rt]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 19:52:50 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 19:07:48 2008'' |
