title: Synthesis, activity, and structural analysis of novel α-hydroxytropolone inhibitors of human immunodeficiency virus reverse transcriptase-associated ribonuclease H.
abstract: The α-hydroxytroplone, manicol (5,7-dihydroxy-2-isopropenyl-9-methyl-1,2,3,4-tetrahydro-benzocyclohepten-6-one), potently and specifically inhibits ribonuclease H (RNase H) activity of human immunodeficiency virus reverse transcriptase (HIV RT) in vitro. However, manicol was ineffective in reducing virus replication in culture. Ongoing efforts to improve the potency and specificity over the lead compound led us to synthesize 14 manicol derivatives that retain the divalent metal-chelating α-hydroxytropolone pharmacophore. These efforts were augmented by a high resolution structure of p66/p51 HIV-1 RT containing the nonnucleoside reverse transcriptase inhibitor (NNRTI), TMC278 and manicol in the DNA polymerase and RNase H active sites, respectively. We demonstrate here that several modified α-hydroxytropolones exhibit antiviral activity at noncytotoxic concentrations. Inclusion of RNase H active site mutants indicated that manicol analogues can occupy an additional site in or around the DNA polymerase catalytic center. Collectively, our studies will promote future structure-based design of improved α-hydroxytropolones to complement the NRTI and NNRTI currently in clinical use.
authors.affiliation: RT Biochemistry Section, HIV Drug Resistance Program, National Cancer Institute-Frederick, Frederick, Maryland 21702, United States.
authors.forename: Suhman
authors.initials: S
authors.lastname: Chung
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Himmel
authors.forename: Jian-Kang
authors.initials: JK
authors.lastname: Jiang
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Wojtak
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Bauman
authors.forename: Jason W
authors.initials: JW
authors.lastname: Rausch
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wilson
authors.forename: John A
authors.initials: JA
authors.lastname: Beutler
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
authors.forename: Stuart F J
authors.initials: SF
authors.lastname: Le Grice
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001567:Benzocycloheptenes / Q000737:chemistry; D020134:Catalytic Domain; D002413:Cations, Divalent; D002460:Cell Line; D056831:Coordination Complexes / Q000737:chemistry; D018360:Crystallography, X-Ray; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008345:Manganese / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D009570:Nitriles / Q000737:chemistry; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry; D054309:Ribonuclease H, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D000068696:Rilpivirine; D013329:Structure-Activity Relationship; D014334:Tropolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D014779:Virus Replication
chemical_list: D019380:Anti-HIV Agents; D001567:Benzocycloheptenes; D002413:Cations, Divalent; D056831:Coordination Complexes; D009570:Nitriles; D011743:Pyrimidines; C497843:manicol; D008345:Manganese; D014334:Tropolone; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D004259:DNA-Directed DNA Polymerase; D054309:Ribonuclease H, Human Immunodeficiency Virus; D000068696:Rilpivirine