Biological targets and mechanisms of action of natural products from marine cyanobacteria

Abstract

Marine cyanobacteria are an ancient group of organisms and prolific producers of bioactive secondary metabolites. These compounds are presumably optimized by evolution over billions of years to exert high affinity for their intended biological target in the ecologically relevant organism but likely also possess activity in different biological contexts such as human cells. Screening of marine cyanobacterial extracts for bioactive natural products has largely focused on cancer cell viability; however, diversification of the screening platform led to the characterization of many new bioactive compounds. Targets of compounds have oftentimes been elusive if the compounds were discovered through phenotypic assays. Over the past few years, technology has advanced to determine mechanism of action (MOA) and targets through reverse chemical genetic and proteomic approaches, which has been applied to certain cyanobacterial compounds and will be discussed in this review. Some cyanobacterial molecules are the most-potent-in-class inhibitors and therefore may become valuable tools for chemical biology to probe protein function but also be templates for novel drugs, assuming in vitro potency translates into cellular and in vivo activity. Our review will focus on compounds for which the direct targets have been deciphered or which were found to target a novel pathway, and link them to disease states where target modulation may be beneficial.

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

“…Over the last two decades, the range of availablem ethods used to identify relevant biological targets and mode of action of small-molecule NPs has changed dramatically.T he discussion is out of the scope of this paper,b ut these methods were reviewed for marine NPs recently. [144,145] Table 2. Strategies to identify bioactive compoundsf rom natural extracts.…”

Comparative mass spectrometry-based metabolomics strategies for the investigation of microbial secondary metabolites

“…39,226 Even after correlating metabolites with biological activity, determining the mode of action for active compounds can be difficult and expensive. 227-230 One approach has been developed that uses the antibiotic spectrum of activities across different organisms, mode of action profiles (BioMAP), to group similar antibiotics. 231 This method was effectively able to cluster antibiotics of the same compound class and led to the identification of a novel naphthoquinone antibiotic, arromycin.…”

Discovery, Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide, a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria

“…The chemical diversity of secondary metabolites reported to date has shown that marine cyanobacteria are an excellent resource for the discovery of new compounds . Furthermore, marine cyanobacteria have been shown to be a source for secondary metabolites with interesting bioactivities and mechanisms of action . In our continuing search for new metabolites from marine cyanobacteria, we have isolated a macrolide xylopyranoside trivially named cocosolide ( 1 ) from the lipophilic extracts of the soft, golden cyanobacterium preliminarily identified as Symploca sp.…”

“…[1] Furthermore, marine cyanobacteria have been shown to be as ource for secondary metabolites with interesting bioactivities and mecha-nisms of action. [2,3] In our continuing search for new metabolites from marinec yanobacteria, we have isolated am acrolide xylopyranosidet rivially namedc ocosolide (1)f rom the lipophilic extractso ft he soft, golden cyanobacterium preliminarily identified as Symploca sp.c ollected from Cocos Lagoona nd Ta nguisson reef flat, Guam. Cocosolide is as ymmetrical dimer, which structurally resembles the sponge metabolites clavosolides A-D isolated from aP hilippine collection of the sponge Myriastrac lavosa [4,5] andc yanolide Ao btained from aP apua New Guinea collectiono fLyngbya bouillonii (Figure 1).…”