No abstract

A new anti-HIV protein, scytovirin, was isolated from aqueous extracts of the cultured cyanobacterium Scytonema varium. The protein displayed potent anticytopathic activity against laboratory strains and primary isolates of HIV-1 with EC50 values ranging from 0.3 to 22 nM. Scytovirin binds to viral coat proteins gp120, gp160, and gp41 but not to cellular receptor CD4 or other tested proteins. This unique protein consists of a single 95-amino acid chain with significant internal sequence duplication and 10 cysteines forming five intrachain disulfide bonds.

The novel cyclic depsipeptides papuamides A (1), B (2), C (3), and D (4) have been isolated from Papua New Guinea collections of the sponges Theonella mirabilis and Theonella swinhoei. Their structures were determined by a combination of spectroscopic analysis and chemical degradation and derivatization studies. In addition to glycine, alanine, and threonine, these peptides contain a number of unusual amino acids including 3,4-dimethylglutamine, β-methoxytyrosine, 3-methoxyalanine, and 2,3-diaminobutanoic acid or 2-amino-2butenoic acid residues. Papuamides A-D (1-4) are also the first marine-derived peptides reported to contain 3-hydroxyleucine and homoproline residues. These peptides also contain a previously undescribed 2,3-dihydroxy-2,6,8-trimethyldeca-(4Z,6E)-dienoic acid moiety N-linked to a terminal glycine residue. Papuamides A (1) and B (2) inhibited the infection of human T-lymphoblastoid cells by HIV-1 RF in vitro with an EC 50 of approximately 4 ng/mL. Compound 1 was also cytotoxic against a panel of human cancer cell lines with a mean IC 50 of 75 ng/mL. Sponges in the genus Theonella (order Lithistida) have been a prolific source of structurally diverse, biologically active peptides. 1 Recent examples of Theonella peptides include polytheonamides, 2 cyclotheonamides, 3 theonellapeptolides, 4 the-onellamides, 5 theonegramides, 6 keramamides, 7 mozamides, 8 mutoporins, 9 microsclerodermins, 10 cupolamide, 11 oriamide, 12 and cyclolithistide A. 13 The biosynthetic origin of compounds isolated from Theonella sponges has often been attributed to symbiotic bacteria or microalgae. Recently, the peptide metabolite theopalauamide 14 was found localized in eubacteria that live symbiotically within Theonella swinhoei. Many Theonelladerived peptides demonstrate potent cytotoxicity, 2,5,11,12 thrombin inhibition, 3 phosphatase inhibition, 9 protease inhibition, 3 or antifungal properties. 5,6,10,13,14 However, there have not been any previous reports of peptides from Theonella that inhibit the human immunodeficiency virus (HIV). The only sponge-* To whom correspondence should be addressed. Michael R. Boyd: phone,

The cyclotides are a recently discovered, structurally unique family of bioactive plant peptides. Their discovery spawned a series of structural analyses, synthetic efforts, and studies to define the biosynthesis and biological properties of these novel peptide metabolites. Cyclotides have a head-to-tail cyclized amino acid backbone and a conserved cystine knot motif that provides an extremely stable structural framework. They all share a common global fold and are highly resistant to denaturation and to cleavage by proteolytic enzymes. However, these macrocyclic peptides are quite permissive to amino acid substitutions or additions in several peripheral loop regions, since changes in these loops do not alter the core cyclotide structure. These features make cyclotides attractive templates for incorporating desired amino acid sequences and then delivering these peptide sequences in a well defined, highly stable framework. Cyclotides likely function in a defensive role in the source plants since they exhibit a broad spectrum of antimicrobial activity and are detrimental to the growth and survival of herbivorous insects. Cyclotides are gene-encoded polypeptides that are cleaved from larger precursor proteins and then cyclized. This review summarizes research done on a subset of cyclotides that were discovered due to their HIV inhibitory properties. It details the isolation and characterization of these compounds and describes this work in the context of our current state of knowledge of the entire cyclotide family.

A 37 amino acid cyclic polypeptide has been isolated from the organic extract of the tropical tree Palicourea condensata. Palicourein (1) is the largest of a growing family of plant peptides that contain a cyclized amino acid backbone cross-linked via three internal disulfide bridges. Palicourein inhibits the in vitro cytopathic effects of HIV-1RF infection of CEM-SS cells with an EC50 value of 0.1 microM and an IC50 value of 1.5 microM.

Bioassay-guided fractionation of an extract of a marine sponge, Stelletta sp., has led to the isolation and characterization of four new cytotoxic isomalabaricane triterpenes, named stellettins C (1), D (2), E (3), and F (4). Three known triterpenes (5-7) were also isolated from the same extract. The most sensitive of the tested cell lines (e.g., leukemia, central nervous system, renal) generally responded with GI50 concentrations in the low-to-mid nanomolar range.

Inhibition of the hypoxia-inducible factor 1α (HIF-1α) pathway by disrupting its association with the transcriptional coactivator p300 inhibits angiogenesis and tumor development. Development of HIF-1α/p300 inhibitors has been hampered by preclinical toxicity; therefore, we aimed to identify novel HIF-1α/p300 inhibitors. Using a cell-free assay designed to test compounds that block HIF-1α/p300 binding, 170 298 crude natural product extracts and prefractionated samples were screened, identifying 25 active extracts. One of these extracts, originating from the marine sponge Latrunculia sp., afforded six pyrroloiminoquinone alkaloids that were identified as positive hits (IC50 values: 1-35 μM). Luciferase assays confirmed inhibition of HIF-1α transcriptional activity by discorhabdin B (1) and its dimer (2), 3-dihydrodiscorhabdin C (3), makaluvamine F (5), discorhabdin H (8), discorhabdin L (9), and discorhabdin W (11) in HCT 116 colon cancer cells (0.1-10 μM, p < 0.05). Except for 11, all of these compounds also reduced HIF-1α transcriptional activity in LNCaP prostate cancer cells (0.1-10 μM, p < 0.05). These effects occurred at noncytotoxic concentrations (<50% cell death) under hypoxic conditions. At the downstream HIF-1α target level, compound 8 (0.5 μM) significantly decreased VEGF secretion in LNCaP cells (p < 0.05). In COLO 205 colon cancer cells no activity was shown in the luciferase or cytotoxicity assays. Pyrroloiminoquinone alkaloids are a novel class of HIF-1α inhibitors, which interrupt the protein-protein interaction between HIF-1α and p300 and consequently reduce HIF-related transcription.

A new carbazole alkaloid, siamenol (1), and two known alkaloids, mahanimbine (2) and mahanimbilol (3), have been isolated from the organic extract of Murraya siamensis. The novel compound exhibited HIV-inhibitory activity.