RESUMO
Quinoxapeptin A and B are novel chromodepsipeptides which were isolated from a nocardioform actinomycete with indeterminant morphology. Quinoxapeptins A and B are potent inhibitors of HIV-1 and HIV-2 reverse transcriptase and almost equally active against two single mutants forms as well as a double mutant form of HIV-1 reverse transcriptase. Quinoxapeptin A and B are specific inhibitors of HIV-1 and HIV-2 reverse transcriptase because they did not inhibit human DNA polymerase alpha, beta, gamma and delta. Quinoxapeptin A and B are structurally similar to luzopeptin A which was also active against HIV-1 and HIV-2 reverse transcriptase.
Assuntos
HIV-1/enzimologia , HIV-2/enzimologia , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacologia , Quinoxalinas/metabolismo , Quinoxalinas/farmacologia , DNA Polimerase Dirigida por RNA/metabolismo , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Actinomycetales/classificação , Actinomycetales/metabolismo , Transcriptase Reversa do HIV , HIV-1/genética , Humanos , Hidroxiquinolinas/química , Hidroxiquinolinas/farmacologia , Técnicas In Vitro , Cinética , Estrutura Molecular , Mutação , Inibidores da Síntese de Ácido Nucleico , Peptídeos Cíclicos/química , Quinoxalinas/química , DNA Polimerase Dirigida por RNA/genética , Inibidores da Transcriptase Reversa/químicaRESUMO
Actinoplanic acids A and B are macrocyclic polycarboxylic acids that are potent reversible inhibitors of farnesyl-protein transferase. Actinoplanic acids A and B were isolated from Actinoplanes sp. MA 7066 while actinoplanic acid B was isolated from both MA 7066 and Streptomyces sp. MA 7099. Actinoplanic acids A and B are competitive with respect to farnesyl diphosphate and are selective inhibitors of farnesyl-protein transferase because they do not inhibit geranylgeranyl-protein transferase type 1 or squalene synthase. MA 7066 is believed to be a novel species of actinomycetes while MA 7099 is believed to be a novel strain of Streptomyces violaceusniger on the basis of morphological, biochemical and chemotaxonomic characteristics as well as its production of actinoplanic acids.
Assuntos
Actinomycetales/química , Alquil e Aril Transferases , Inibidores Enzimáticos/isolamento & purificação , Lactonas/isolamento & purificação , Streptomyces/química , Transferases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase , Lactonas/farmacologiaRESUMO
L-689,502 is a potent inhibitor of HIV-1 protease activity in vitro. Microbial biotransformations of L-689,502 by cultures belonging to the genus Streptomyces sp. were performed. Extracts of culture broths were examined for the production of metabolites of L-689,502 that could inhibit HIV-1 protease activity. One culture, MA 6804 (Streptomyces lavendulae, ATCC 55095), produced L-694,746 that, while being structurally related to L-689,502, is a novel metabolite and a potent inhibitor of HIV-1 protease.
Assuntos
Inibidores da Protease de HIV , HIV-1/enzimologia , Morfolinas/farmacologia , Peptídeos/farmacologia , Inibidores de Proteases/farmacologia , Sequência de Aminoácidos , Biotransformação , Cromatografia Líquida de Alta Pressão , Cinética , Dados de Sequência Molecular , Estrutura Molecular , Morfolinas/metabolismo , Oligopeptídeos/síntese química , Oligopeptídeos/metabolismo , Pepstatinas/farmacologia , Peptídeos/metabolismo , Streptomyces/metabolismoRESUMO
The discovery and physico-chemical characterization of three novel and minor virginiamycin M1 analogs as potent gastrin antagonists from a culture of a strain of Streptomyces olivaceus are described. These analogs are L-156,586, L-156,587 and L-156,588. They are, respectively, 15-dihydro-13,14-anhydro-, 13,14-anhydro- and 13-desoxy-analogs of virginiamycin M1. We also chemically converted virginiamycin M1 (via L-156,587) to L-156,586 and its unnatural epimer, L-156,906. These analogs are competitive and selective antagonists of gastrin and brain cholecystokinin binding at nanomolar concentrations. These are the most potent gastrin/brain cholecystokinin antagonists from natural products. The same compounds showed poor Gram-positive antibiotic activity versus virginiamycin M1. Structurally related Gram-positive antibiotics, griseoviridin and madumycin I, were inactive in gastrin and brain cholecystokinin binding at up to 100 microM.