Mirabamides A-D, depsipeptides from the sponge siliquariaspongia mirabilis that inhibit HIV-1 fusion

Four new cyclic depsipeptides termed mirabamides A-D (1-4) have been isolated from the marine sponge Siliquariaspongia mirabilis and shown to potently inhibit HIV- 1 fusion. Their structures were elucidated by NMR and ESIMS, and absolute stereochemistry of the amino acids was determined using advanced Marfey's methods and NMR. Mirabamides contain two new entities, including 4-chlorohomoproline in 1-3 and an unusual glycosylated amino acid, beta-methoxytyrosine 4'-O-alpha-L-rhamnopyranoside (in 1, 2, and 4), along with a rare N-terminal aliphatic hydroxy acid. These elements proved to be useful for anti-HIV structure-activity relationship studies. Mirabamide A inhibited HIV-1 in neutralization and fusion assays with IC50 values between 40 and 140 nM, as did mirabamides C and D (IC50 values between 140 nM and 1.3 mu M for 3 and 190 nM and 3.9,mu M for 4), indicating that these peptides can act at the early stages of HIV- I entry. The potent activity of depsipeptides containing the glycosylated beta-OMe Tyr unit demonstrates that beta-OMe Tyr itself is not critical for activity. Mirabamides A-C inhibited the growth of B. subtilis and C. albicans at 1-5 mu g/disk in disk diffusion assays.