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.

Fig. 1

The structure of brentuximab vedotin (Adcetris). The small molecule portion, monomethyl auristatin E, is designed based on the cyanobacterial molecule dolastatin 10.

Fig. 2

Screening platforms for bioactivity assessment, mechanism of action and target identification of small molecules from marine cyanobacteria.

Fig. 3

MOA of tubulin-targeting agents. Tubulin-disrupting compounds from marine cyanobacteria cause significant cellular microtubule depolymerization, leading to G2 cell cycle arrest and cell death.

Fig. 4

Tubulin-targeting agents from marine cyanobacteria.

Fig. 5

Actin-targeting agents from marine cyanobacteria.

Fig. 6

Small molecules from marine cyanobacteria acting on non-classical cancer cell targets.

Fig. 7

MOA of HDAC inhibitors. Cell cycle arrest and apoptosis mediated by HDAC inhibitors are in part due to alteration in gene expression arising from changes in acetylation levels of histone and non-histone proteins.

Fig. 8

Selective DPP8 and elastase inhibitors from marine cyanobacteria. The 2-amino-butenoic acid moiety (red) of modified cyanobacterial cyclodepsipeptides serves as the warhead in inhibiting elastase while other modified amino acid residues (blue) provides additional key interactions.

Fig. 9

MOA of elastase inhibitors from marine cyanobacteria. Elastase inhibitors from marine cyanobacteria modulate the transcriptional and post-translational effects of elastase in bronchial epithelial cells leading to significant cytoprotection from elastase-induced cell detachment and anti-proliferation.

Fig. 10

Structure and bioactivity of cathepsin E inhibitors. A. Cathepsin E inhibitors from marine cyanobacteria. B. Selectivity profile of grassystatin A against metalloproteases and aspartic proteases. Grassystatin A did not inhibit members of other families of proteases such as serine and cysteine proteases, dipeptidyl/tripeptidyl peptidases and cysteine carboxypeptidases. C. Key molecular interactions between grassystatin A and cathepsin E. Reprinted with permission from J. C. Kwan, E. A. Eksioglu, C. Liu, V. J. Paul and H. Luesch, J. Med. Chem., 2009, 52, 5732–5747. Copyright 2009 American Chemical Society.

Fig. 11

Design of new BACE1 inhibitor based on the cyanobacterial compound tasiamide B.

Fig. 12

Structures of modulators of voltage-gated ion channels from marine cyanobacteria.

Fig. 13

Protozoal parasite targeting compounds from marine cyanobacteria and their MOA.

Fig. 14

Structures of quorum sensing inhibitors from marine cyanobacteria.

Fig. 15

Bifunctional molecules from marine cyanobacteria and the MOA pitinoic acid B and the corresponding component fatty acids.