title: Synthesis and structure-activity relationship studies of HIV-1 virion infectivity factor (Vif) inhibitors that block viral replication.
abstract: The human immunodeficiency virus 1 (HIV-1) virion infectivity factor (Vif) protein, essential for in vivo viral replication, protects the virus from innate antiviral cellular factor apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G (APOBEC3G; A3G) and is an attractive target for the development of novel antiviral therapeutics. We have evaluated the structure-activity relationships of N-(2-methoxyphenyl)-2-((4-nitrophenyl)thio)benzamide (RN-18), a small molecule recently identified as an inhibitor of Vif function that blocks viral replication only in nonpermissive cells expressing A3G, by inhibiting Vif-A3G interactions. Microwave-assisted cross-coupling reactions were developed to prepare a series of RN18 analogues with diverse linkages and substitutions on the phenyl rings. A dual cell-based assay system was used to assess antiviral activity against wild-type HIV-1 in both nonpermissive (H9) and permissive (MT4) cells that also allowed evaluation of specificity. In general, variations of phenyl substitutions were detrimental to antiviral potency and specificity, but isosteric replacements of amide and ether linkages were relatively well tolerated. These structure-activity relationship data define structural requirements for Vif-specific activity, identify new compounds with improved antiviral potency and specificity, and provide leads for further exploration to develop new antiviral therapeutics.
authors.affiliation: Chemical Biology Program, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
authors.forename: Akbar
authors.initials: A
authors.lastname: Ali
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Robin S
authors.initials: RS
authors.lastname: Nathans
authors.forename: Hong
authors.initials: H
authors.lastname: Cao
authors.forename: Natalia
authors.initials: N
authors.lastname: Sharova
authors.forename: Mario
authors.initials: M
authors.lastname: Stevenson
authors.forename: Tariq M
authors.initials: TM
authors.lastname: Rana
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development*; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D054320:vif Gene Products, Human Immunodeficiency Virus