title: HIV-1 reverse transcriptase structure with RNase H inhibitor dihydroxy benzoyl naphthyl hydrazone bound at a novel site.
abstract: The rapid emergence of drug-resistant variants of human immunodeficiency virus, type 1 (HIV-1), has limited the efficacy of anti-acquired immune deficiency syndrome (AIDS) treatments, and new lead compounds that target novel binding sites are needed. We have determined the 3.15 A resolution crystal structure of HIV-1 reverse transcriptase (RT) complexed with dihydroxy benzoyl naphthyl hydrazone (DHBNH), an HIV-1 RT RNase H (RNH) inhibitor (RNHI). DHBNH is effective against a variety of drug-resistant HIV-1 RT mutants. While DHBNH has little effect on most aspects of RT-catalyzed DNA synthesis, at relatively high concentrations it does inhibit the initiation of RNA-primed DNA synthesis. Although primarily an RNHI, DHBNH binds >50 A away from the RNH active site, at a novel site near both the polymerase active site and the non-nucleoside RT inhibitor (NNRTI) binding pocket. When DHBNH binds, both Tyr181 and Tyr188 remain in the conformations seen in unliganded HIV-1 RT. DHBNH interacts with conserved residues (Asp186, Trp229) and has substantial interactions with the backbones of several less well-conserved residues. On the basis of this structure, we designed substituted DHBNH derivatives that interact with the NNRTI-binding pocket. These compounds inhibit both the polymerase and RNH activities of RT.
authors.affiliation: Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854-5627, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Himmel
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Sarafianos
authors.forename: Sanjeewa
authors.initials: S
authors.lastname: Dharmasena
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Hossain
authors.forename: Kessler
authors.initials: K
authors.lastname: McCoy-Simandle
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ilina
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Clark
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Knight
authors.forename: John G
authors.initials: JG
authors.lastname: Julias
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Clark
authors.forename: Karsten
authors.initials: K
authors.lastname: Krogh-Jespersen
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Levy
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
authors.forename: Michael A
authors.initials: MA
authors.lastname: Parniak
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
mesh_terms: D045744:Cell Line, Tumor; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D017433:Protein Structure, Secondary / Q000187:drug effects / Q000502:physiology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D016914:Ribonuclease H / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D006835:Hydrazones; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H