title: Optimization of unique, uncharged thioesters as inhibitors of HIV replication.
abstract: A combinatorial chemistry approach was employed to prepare a restricted library of N-substituted S-acyl-2-mercaptobenzamide thioesters. It was shown that many members of this chemotype display anti-HIV activity via their ability to interact with HIV-1, HIV-2, SIV-infected cells, cell-free virus, and chronically and latently infected cells in a manner consistent with targeting of the highly conserved HIV-1 NCp7 zinc fingers. Compounds were initially screened using two different in vitro antiviral assays and evaluated for stability in neutral buffer containing 10% pooled human serum using a spectrophotometric assay. These data revealed that there was no significant correlation between thioester stability and antiviral activity, however, a slight inverse correlation between serum stability and virucidal activity was noted. Based on the virucidal capability and the ability to select lead compounds to inhibit virus expression from latently infected TNFalpha-induced U1 cells, we next determined if these compounds could prevent HIV cell-to-cell transmission. Several thioesters demonstrated potent inhibition of HIV cell-to-cell transmission with EC50 values in the 80-100 nM range. Thus, we have optimized a series of restricted thioesters and provided evidence that serum stability is not required for antiviral activity. Moreover, selected compounds show potential for development as topical microbicides.
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA.
authors.forename: Pratibha
authors.initials: P
authors.lastname: Srivastava
authors.forename: Marco
authors.initials: M
authors.lastname: Schito
authors.forename: Rasem J
authors.initials: RJ
authors.lastname: Fattah
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hara
authors.forename: Tracy
authors.initials: T
authors.lastname: Hartman
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buckheit
authors.forename: Jim A
authors.initials: JA
authors.lastname: Turpin
authors.forename: John K
authors.initials: JK
authors.lastname: Inman
authors.forename: Ettore
authors.initials: E
authors.lastname: Appella
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques; D004355:Drug Stability; D004952:Esters / Q000138:chemical synthesis* / Q000494:pharmacology; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000821:virology; D008826:Microbial Sensitivity Tests; D009000:Monocytes / Q000821:virology; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D004952:Esters; D013438:Sulfhydryl Compounds