Media Gallery

Marine natural product on target: GPCRs are prime targets for drug discovery, representing targets of over 40% of approved drugs. The cover illustrates tumonolide, a new marine natural product, docked into the binding pocket of the tachykinin receptor 2 (TACR2). The TACR2-selective GPCR inhibitor was isolated from a marine cyanobacterium, and its structure, including the absolute configuration depicted on the ocean floor, was elucidated through various spectroscopic and computational methods.

Dolastatin 10, a potent tubulin-targeting marine anticancer natural product, provided the basis for the development of six FDA-approved antibody–drug conjugates. Through the screening of cyanobacterial Caldora penicillata environmental DNA libraries and metagenome sequencing, we identified its biosynthetic gene cluster. Functional prediction of 10 enzymes encoded in the 39 kb cluster supports the dolastatin 10 biosynthesis. The nonheme diiron monooxygenase DolJ was biochemically characterized to mediate the terminal thiazole formation in dolastatin 10.

Lyngbyastatin (Lbn) 1 and 3 were identified from the field-collected marine cyanobacterium Okeania sp. Their biosynthetic gene cluster was predicted from the metagenome-assembled genome and confirmed by bioinformatic analysis and biochemical studies of selected adenylation domains. Two Lbn-like gene clusters were further mined from publicly available cyanobacterial genomes.

Apratoxin S4 in action against SARS-CoV-2: This host-directed antiviral shuts off spike protein production and trafficking (top) and prevents double membrane vesicle formation and assembly of progeny virions (bottom).

Surfing across the blood-brain barrier with a purpose and a splash: The marine natural product and potent class I HDAC inhibitor largazole has activity against glioblastoma cells and induces neuroprotective and antiproliferative functional responses in the brain through modulation of gene expression of entire networks underlying CNS diseases.

The cover image illustrates the multidisciplinary research that linked a natural product discovered from the depicted marine cyanobacteria to GPCR modulation. The portrayed peptide, amantamide, was isolated, synthesized, and characterized as a selective CXCR7 agonist. Molecular modeling of amantamide provides the starting point for rational optimization.

The cover feature picture shows Ahp-cyclodepsipeptides, the producing marine cyanobacterium overgrowing a coral, and the compounds’ anticancer effects. These cyclodepsipeptides inhibit human neutrophil elastase and, as a consequence, the migration of invasive breast cancer cells through the modulation of gene expression and proteolytic processing of membrane proteins.

Small molecules that modulate histone acetylation by targeting key enzymes mediating this posttranslational modification – histone acetyltransferases and histone deacetylases – are validated chemotherapeutic agents for the treatment of cancer. Secondary metabolites from various biological sources target this epigenetic modification through distinct mechanisms of enzyme regulation by utilizing a diverse array of pharmacophores. We review the discovery of these compounds and discuss their modes of inhibition together with their downstream biological effects.

Natural products are secondary metabolites that confer survival advantages to the producing organism. Many require activation before they exert their biological effects, perhaps as part of the organism's self‐resistance strategy or to aid targeted delivery. In this Concept article Luesch and Kwan outline several examples of “Weapons in Disguise”, natural products that use protecting group chemistry or intricate chemical cascades for activation beyond simple “prodrug” paradigms.

The Luesch lab previously described the bioassay-guided isolation, structure determination, synthesis, and target identification of largazole, a marine-derived antiproliferative natural product that is a prodrug that releases the most potent natural inhibitor of class I histone deacetylases (HDACs), validated targets for cancer therapy. The cover highlights structure-activity studies using biochemical and molecular docking approaches. The article describes the characterization of the anticancer activity of largazole using in vitro and in vivo cancer models, including comparative transcriptomics, pharmacology, biochemical validation, stability, and efficacy studies.

Hendrik Luesch’s discovery of largazole and its producing cyanobacterium are featured in this annual Marine Natural Products review and on the journal cover, respectively.

Genome-scale analysis has been extended from gene expression profiling to parallel cell-based functional profiling, allowing the characterization of gene function and small molecule actions in yeast and in mammalian cells.

This is the first report that uses an unbiased functional genomics approach in cancer cells to study the mode of action of a potent cyanobacterial cytotoxin and also visualizes “apratoxin A in action” in zebrafish.