title: Crystal structures for HIV-1 reverse transcriptase in complexes with three pyridinone derivatives: a new class of non-nucleoside inhibitors effective against a broad range of drug-resistant strains.
abstract: 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.
authors.affiliation: Center for Advanced Biotechnology and Medicine (CABM) and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Himmel
authors.forename: Kalyan
authors.initials: K
authors.lastname: Das
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Clark
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
authors.forename: Abdellah
authors.initials: A
authors.lastname: Benjahad
authors.forename: Said
authors.initials: S
authors.lastname: Oumouch
authors.forename: Jérôme
authors.initials: J
authors.lastname: Guillemont
authors.forename: Sophie
authors.initials: S
authors.lastname: Coupa
authors.forename: Alain
authors.initials: A
authors.lastname: Poncelet
authors.forename: Imre
authors.initials: I
authors.lastname: Csoka
authors.forename: Christophe
authors.initials: C
authors.lastname: Meyer
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: Chi Hung
authors.initials: CH
authors.lastname: Nguyen
authors.forename: David S
authors.initials: DS
authors.lastname: Grierson
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
mesh_terms: D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011728:Pyridones / Q000737:chemistry*; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry*
chemical_list: D011728:Pyridones; C507714:R 157208; C507715:R 165481; C507716:R 221239; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase