title: Derivatives of 5-nitro-furan-2-carboxylic acid carbamoylmethyl ester inhibit RNase H activity associated with HIV-1 reverse transcriptase.
abstract: The RNase H activity associated with human immunodeficiency virus type 1 (HIV-1) is an attractive target for an antiretroviral drug development. We screened 20000 small-molecular-weight compounds for RNase H inhibitors and identified a novel RNase H-inhibiting structure characterized by a 5-nitro-furan-2-carboxylic acid carbamoylmethyl ester (NACME) moiety. Two NACME derivatives, 5-nitro-furan-2-carboxylic acid adamantan-1-carbamoylmethyl ester (compound 1) and 5-nitro-furan-2-carboxylic acid [[4-(4-bromo-phenyl)-thiazol-2-yl]-(tetrahydro-furan-2-ylmethyl)-carbamoyl]-methyl ester (compound 2), effectively blocked HIV-1 and MLV RT-associated RNase H activities with IC(50)s of 3-30 microM but had little effect on bacterial RNase H activity in vitro. Additionally, 20-25 microM compound 2 effectively inhibited HIV-1 replication. An in silico docking simulation indicated that the conserved His539 residue, and two metal ions in the RNase H catalytic center are involved in RNase H inhibition by NACME derivatives. Taken together, these data suggest that NACME derivatives may be potent lead compounds for development of a novel class of antiretroviral drugs.
authors.affiliation: Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Inage-ku, Chiba, Japan.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Fuji
authors.forename: Emiko
authors.initials: E
authors.lastname: Urano
authors.forename: Yuko
authors.initials: Y
authors.lastname: Futahashi
authors.forename: Makiko
authors.initials: M
authors.lastname: Hamatake
authors.forename: Junko
authors.initials: J
authors.lastname: Tatsumi
authors.forename: Tyuji
authors.initials: T
authors.lastname: Hoshino
authors.forename: Yuko
authors.initials: Y
authors.lastname: Morikawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Jun
authors.initials: J
authors.lastname: Komano
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054309:Ribonuclease H, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D005663:Furans; D018894:Reverse Transcriptase Inhibitors; D054309:Ribonuclease H, Human Immunodeficiency Virus