title: Dicaffeoylquinic acid inhibitors of human immunodeficiency virus integrase: inhibition of the core catalytic domain of human immunodeficiency virus integrase.
abstract: Integration of a cDNA copy of the human immunodeficiency virus (HIV) genome is mediated by an HIV-1-encoded enzyme, integrase (IN), and is required for productive infection of CD4+ lymphocytes. It had been shown that 3,5-dicaffeoylquinic acid and two analogues were potent and selective inhibitors of HIV-1 IN in vitro. To determine whether the inhibition of IN by dicaffeoylquinic acids was limited to the 3,5 substitution, 3,4-, 4,5-, and 1,5-dicaffeoylquinic acids were tested for inhibition of HIV-1 replication in tissue culture and inhibition of HIV-1 IN in vitro. All of the dicaffeoylquinic acids were found to inhibit HIV-1 replication at concentrations ranging from 1 to 6 microM in T cell lines, whereas their toxic concentrations in the same cell lines were > 120 microM. In addition, the compounds inhibited HIV-1 IN in vitro at submicromolar concentrations. Molecular modeling of these ligands with the core catalytic domain of IN indicated an energetically favorable reaction, with the most potent inhibitors filling a groove within the predicted catalytic site of IN. The calculated change in internal free energy of the ligand/IN complex correlated with the ability of the compounds to inhibit HIV-1 IN in vitro. These results indicate that the dicaffeoylquinic acids as a class are potent and selective inhibitors of HIV-1 IN and form important lead compounds for HIV drug discovery.
authors.affiliation: Department of Pathology, University of California, Irvine 92697-4800, USA. ewrobine@uci.edu
authors.forename: W E
authors.initials: WE
authors.lastname: Robinson
authors.forename: M
authors.initials: M
authors.lastname: Cordeiro
authors.forename: S
authors.initials: S
authors.lastname: Abdel-Malek
authors.forename: Q
authors.initials: Q
authors.lastname: Jia
authors.forename: S A
authors.initials: SA
authors.lastname: Chow
authors.forename: M G
authors.initials: MG
authors.lastname: Reinecke
authors.forename: W M
authors.initials: WM
authors.lastname: Mitchell
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001665:Binding Sites; D002384:Catalysis; D002726:Chlorogenic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D017124:Conserved Sequence; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D006801:Humans; D007536:Isomerism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D016662:Virus Integration / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D019428:HIV Integrase Inhibitors; D002726:Chlorogenic Acid; D019427:HIV Integrase; C100434:3,5-dicaffeoylquinic acid