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 microM for 3 and 190 nM and 3.9 microM for 4), indicating that these peptides can act at the early stages of HIV-1 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 microg/disk in disk diffusion assays.
Plaza
Alberto
A
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0820, USA.
Gustchina
Elena
E
Baker
Heather L
HL
Kelly
Michelle
M
Bewley
Carole A
CA
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D047630:Depsipeptides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D008386:Marine Biology; D008826:Microbial Sensitivity Tests; D008849:Micronesia; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011161:Porifera / Q000737:chemistry*
D000900:Anti-Bacterial Agents; D047630:Depsipeptides