title: Structure-based design, synthesis, and biological evaluation of novel inhibitors of human cyclophilin A.
abstract: Cyclophilin A is involved in many cellular processes, including protein folding and intracellular transports. Because cyclophilin A has been shown to interact with HIV-1 gag proteins and to enhance the viral infectivity, nonimmunosuppressive cyclophilin A ligands may represent a new class of therapeutic agents against HIV. Here, we report a virtual screening using structure- and pharmacophore-based design to identify original nonpeptidic cyclophilin ligands. Following a lead identification of compounds 1 [1-(3-benzyloxypyridin-2-yl)-3-(3-chlorophenyl)urea] and 2 [1-(3-benzyloxypyridin-2-yl)-3-(3-trifluoromethylphenyl)urea] (IC(50) = 0.3 microM), a series of molecules were synthesized from a diarylurea scaffold and evaluated for their in vitro ability to inhibit the cis-trans isomerase activity of cyclophilin A. Molecular modifications provided several more potent compounds, in particular analogues 4d and 4i with IC(50) of 14 and 20 nM, respectively. Then, we evaluated the effect of analogues 1 and 2 on HIV virion infectivity in both immortalized and primary cells. Both 1 and 2 reduced virion infectivity in the replication-defective one-round infection assay, but only 1 impaired wild-type HIV infection in human peripheral blood mononuclear cells.
authors.affiliation: Centre de Biochimie Structurale, UMR 5048 CNRS, UMR 554 INSERM, UM1, Faculté de Pharmacie, BP14491, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Guichou
authors.forename: Julien
authors.initials: J
authors.lastname: Viaud
authors.forename: Clément
authors.initials: C
authors.lastname: Mettling
authors.forename: Guy
authors.initials: G
authors.lastname: Subra
authors.forename: Yea-Lih
authors.initials: YL
authors.lastname: Lin
authors.forename: Alain
authors.initials: A
authors.lastname: Chavanieu
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002478:Cells, Cultured; D021984:Cyclophilin A / Q000037:antagonists & inhibitors*; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014771:Virion / Q000187:drug effects
chemical_list: C508988:1-(3-benzyloxypyridin-2-yl)-3-(3-chlorophenyl)urea; C508989:1-(3-benzyloxypyridin-2-yl)-3-(3-trifluoromethylphenyl)urea; D019380:Anti-HIV Agents; D008024:Ligands; D010671:Phenylurea Compounds; D011725:Pyridines; D021984:Cyclophilin A