SRR-SB3, A DISULFIDE-CONTAINING MACROLIDE THAT INHIBITS A LATE-STAGE OF THE REPLICATIVE CYCLE OF HUMAN-IMMUNODEFICIENCY-VIRUS

From a series of macrocyclic diamides possessing the disulfide linkage , only SRR-SB3, a compound that complexes with zinc, was found to inhi bit human immunodeficiency virus type I (HIV-1; strain IIIB) replicati on at a concentration of 1.8 to 6.5 mu g/ml in MT-4, CEM, and peripher al blood mononuclear cells. SRR-SB3 was toxic to MT-4 cells at a conce ntration of 15.9 mu g/ml, resulting in a selectivity index of 9 in the se 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 transcrip tase inhibitors. It was also active against various HIV-2 strains, sim ian 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. T he compound in combination with other antiviral agents, such as zidovu dine, zalcitabine, and stavudine, showed an effect that was between ad ditive and synergistic. Time-of-addition experiments indicated that SR R-SB3 acts at a late stage of the HIV-1 replicative cycle.