title: SRR-SB3, a disulfide-containing macrolide that inhibits a late stage of the replicative cycle of human immunodeficiency virus.
abstract: From a series of macrocyclic diamides possessing the disulfide linkage, only SRR-SB3, a compound that complexes with zinc, was found to inhibit human immunodeficiency virus type 1 (HIV-1; strain IIIB) replication at a concentration of 1.8 to 6.5 micrograms/ml in MT-4, CEM, and peripheral blood mononuclear cells. SRR-SB3 was toxic to MT-4 cells at a concentration of 15.9 micrograms/ml, resulting in a selectivity index of 9 in these cells. This macrolide was also effective against various other HIV-1 strains, including clinical isolates and HIV-1 strains resistant to protease inhibitors and nucleoside and nonnucleoside reverse transcriptase inhibitors. It was also active against various HIV-2 strains, simian immunodeficiency virus (strain MAC251), and Moloney murine sarcoma virus, but not against viruses other than retroviruses. In addition, the compound was found to inhibit chronic HIV-1 infections in vitro. The compound in combination with other antiviral agents, such as zidovudine, zalcitabine, and stavudine, showed an effect that was between additive and synergistic. Time-of-addition experiments indicated that SRR-SB3 acts at a late stage of the HIV-1 replicative cycle.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Witvrouw
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: C
authors.initials: C
authors.lastname: Pannecouque
authors.forename: S
authors.initials: S
authors.lastname: Jhaumeer-Laulloo
authors.forename: J A
authors.initials: JA
authors.lastname: Esté
authors.forename: D
authors.initials: D
authors.lastname: Schols
authors.forename: P
authors.initials: P
authors.lastname: Cherepanov
authors.forename: J C
authors.initials: JC
authors.lastname: Schmit
authors.forename: Z
authors.initials: Z
authors.lastname: Debyser
authors.forename: A M
authors.initials: AM
authors.lastname: Vandamme
authors.forename: J
authors.initials: J
authors.lastname: Desmyter
authors.forename: S R
authors.initials: SR
authors.lastname: Ramadas
authors.forename: E
authors.initials: E
authors.lastname: de Clercq
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002460:Cell Line; D004279:DNA, Viral / Q000032:analysis; D004220:Disulfides / Q000494:pharmacology*; D004357:Drug Synergism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D051379:Mice; D008980:Moloney murine sarcoma virus / Q000187:drug effects; D016133:Polymerase Chain Reaction; D012192:Retroviridae Infections / Q000188:drug therapy / Q000821:virology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000821:virology; D014412:Tumor Virus Infections / Q000188:drug therapy / Q000821:virology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D001549:Benzamides; D004279:DNA, Viral; D004220:Disulfides; D018894:Reverse Transcriptase Inhibitors; C105415:SRR SB3