Mirabamides A–D, Depsipeptides from the Sponge Siliquariaspongia mirabilis That Inhibit HIV-1 Fusion

Abstract

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.

The first total synthesis of the cyclodepsipeptide pipecolidepsin A

“…This b-branched framework, which characterizes all the members of this new class of non-ribosomal cyclodepsipeptides 5 , comprises the following: a 22-or a 25-membered macrolactone; the presence of complex and rare amino acids; a branching position occupied by a D-allo-b-hydroxy-a-amino acid acylated by the unique (2S,3S,4R)-3,4-dimethylglutamine (diMeGln) residue; and an N-terminus coupled to a saturated or unsaturated b-hydroxy acid. Examples of members of this family include callipeltin A 6 , papuamides 7,8 , neamphamides [9][10][11] , theopapuamides 12,13 , mirabamides 14,15 and homophymines 16,17 . Of note, all of them show relevant therapeutic profiles, mostly including potent cytotoxic and anti-HIV activities.…”

A Spirulina maxima-derived peptide inhibits HIV-1 infection in a human T cell line MT4

“…The marine peptides have been found to mainly inhibit viral entry through membrane fusion (Plaza et al, 2007 and2009;Zampella et al, 2008;Oku et al, 2004). The present study showed that a peptide isolated from S. maxima (SM-peptide) is noncytotoxic and inhibits HIV-1 IIIB -induced cell lysis, reverse transcriptase activity, and viral p24 antigen production.…”

“…Marine materials such as phlorotannins, sulfated chitoolifosaccharides, sulfated polysaccharides, and lectin have been reported to have anti-HIV activities. Additionally, several recent studies have reported that peptides from marine organisms can act as anti-HIV agents because of their therapeutic potential in the treatment of infectious diseases (Plaza et al, 2007 and2009). In this regard, we examined anti-HIV activities of our previously isolated peptides from several marine organisms and found that a peptide from Spirulina maxima (SM-peptide) inhibits HIV-1 infection in human T cell line MT4.…”

Peptide‐Based Inhibitors of Enzymes

“…This cocktail approach is advantageous because it may be tailored to a given patient's drug resistances, resulting in viral loads low enough to significantly suppress (95%) disease transfer between infected mother to prenatal child [26]. The successes of HAART and further advances in HIV-1 protease inhibition secure peptide-based inhibitors as a predominant success story for computational inhibitor design, from the initial development of saquinavir [25] to raltegravir [33] and beyond.…”