RESUMO
Eight new cyanopeptolins (insulapeptolides A-H) were obtained from the cyanobacterium Nostoc insulare. Their isolation was guided by their bioactivity toward the target enzyme human leukocyte elastase, molecular biological investigations, and MALDI-TOF analysis. These peptides are selective inhibitors of human leukocyte elastase with activities in the nanomolar range. Insulapeptolide D was the most potent compound with an IC(50) value of 85 nM (K(i) value of 36 nM).
Assuntos
Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Elastase de Leucócito/antagonistas & inibidores , Nostoc/química , Peptídeos Cíclicos/isolamento & purificação , Peptídeos Cíclicos/farmacologia , Sequência de Aminoácidos , Bioensaio , Catepsina G , Catepsinas/antagonistas & inibidores , Catepsinas/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Elastase de Leucócito/metabolismo , Espectroscopia de Ressonância Magnética , Mieloblastina/antagonistas & inibidores , Mieloblastina/metabolismo , Peptídeos Cíclicos/química , Serina Endopeptidases/metabolismo , Especificidade por SubstratoRESUMO
The cyanobacterium Tychonema sp. produces the new cyclic hexapeptides brunsvicamide A-C (1-3). Brunsvicamide B (2) and C (3) selectively inhibit the Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB), a potential drug target for tuberculosis therapy for which no inhibitors are known to date. Brunsvicamide C contains an N-methylated N'-formylkynurenine moiety, a unique structural motif in cyclic peptides. The new peptides are related to the sponge-derived mozamides, supporting the suggestion that secondary metabolites of certain marine invertebrates are produced by associated microorganisms. Thus, microorganisms phylogenetically related to symbionts of marine invertebrates can be judged as a means to supply "marine-like" compounds for drug development.