title: Specific features of HIV-1 integrase inhibition by bisphosphonate derivatives.
abstract: The integration of viral DNA into the cell genome is one of the key steps in the replication cycle of human immunodeficiency virus type 1 (HIV-1). Therefore, the viral enzyme integrase (IN) catalyzing this process is of great interest as a target for new antiviral agents. We performed a structural-functional analysis of five different series of methylenebisphosphonates (BPs), PO3H2-C(R)(X)-PO3H2, as IN inhibitors with the goal of assessing structural elements required for the inhibitory activity. We found that IN is inhibited only by BP bearing a chlorobenzyl substituent R at the bridging carbon of the P-C-P backbone. These BP inhibited both IN-catalyzed reactions with similar efficacies. They were also active toward some INs with mutations characteristic for HIV-1 strains resistant to strand transfer inhibitors. The study of the mechanism of the IN inhibition by various BP showed that it is effected by the nature of the second substituent (X) at the bridging carbon. Among the tested compounds, only the BP with the amino group bound directly to the BP bridging carbon was found to be a noncompetitive inhibitor and, hence, it can be promising for further studies as potential inhibitor of the IN activity within the preintegration complex.
authors.affiliation: Lomonosov Moscow State University, Chemistry Department and Belozersky Institute of Physical and Chemical Biology, Moscow, Russia.
authors.forename: Julia
authors.initials: J
authors.lastname: Agapkina
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia. Electronic address: JDmitry@hotmail.com.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Yanvarev
authors.affiliation: Lomonosov Moscow State University, Chemistry Department and Belozersky Institute of Physical and Chemical Biology, Moscow, Russia.
authors.forename: Andrey
authors.initials: A
authors.lastname: Anisenko
authors.affiliation: Lomonosov Moscow State University, Chemistry Department and Belozersky Institute of Physical and Chemical Biology, Moscow, Russia.
authors.forename: Sergey
authors.initials: S
authors.lastname: Korolev
authors.affiliation: School of Pharmacy, Biocenter Kuopio, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jouko
authors.initials: J
authors.lastname: Vepsäläinen
authors.affiliation: Lomonosov Moscow State University, Chemistry Department and Belozersky Institute of Physical and Chemical Biology, Moscow, Russia; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Sergey
authors.initials: S
authors.lastname: Kochetkov
authors.affiliation: Lomonosov Moscow State University, Chemistry Department and Belozersky Institute of Physical and Chemical Biology, Moscow, Russia.
authors.forename: Marina
authors.initials: M
authors.lastname: Gottikh
mesh_terms: D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D024882:Drug Resistance, Viral; D004926:Escherichia coli / Q000235:genetics; D019427:HIV Integrase / Q000235:genetics; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004164:Diphosphonates; D019428:HIV Integrase Inhibitors; D019427:HIV Integrase
keywords: Bisphosphonates; HIV; Inhibitors; Integrase; SAR