Chemistry and Biology of the Aeruginosin Family of Serine Protease Inhibitors

Abstract

The aeruginosins have been isolated from marine sponges and cyanobacterial waterblooms, sources that are phylogenetically distinct and the bodies of water are geographically well-separated. The aeruginosins comprise a central hydroxy- (or dihydroxy-) octahydroindole carboxamide core unit, onto which are appended unusual amino acids on the carboxy and amino termini as part of the linear peptide array. Potent inhibitory activity of serine proteases in vitro is exhibited by some of the aeruginosins as a result of the presence and proper deployment of three important pharmacophoric subunits: a P1 arginine mimetic, and two hydrophobic residues with interaction sites designated as P2 and P3. In this article, we provide the first comprehensive review on the chemistry and biology of the aeruginosins, with an emphasis on their sources, structural revisions, and total syntheses.

Enantioselective Synthesis of the Core of Banyaside, Suomilide, and Spumigin HKVV

“…[2] The tricyclic azabicyclononane core common to these is densely functionalized with six stereogenic centers and incorporates glycosyl as well as peptide side-chains at its periphery. The biological activity along with the sheer complexity of the structure renders these notable as targets for synthesis studies.…”

“…Banyaside A (3) and B (4), suomilide (1), and spumigin HKVV (2) [1] are novel natural products belonging to the aeruginosin family of serine protease inhibitors (Scheme 1). [2] The tricyclic azabicyclononane core common to these is densely functionalized with six stereogenic centers and incorporates glycosyl as well as peptide side-chains at its periphery.…”

Plasticity and Evolution of Aeruginosin Biosynthesis in Cyanobacteria

“…1). Most aeruginosins are strong inhibitors of serine proteases (7), and the inhibiting mechanisms have been elucidated by X-ray crystallography of aeruginosin-protease complexes (14,37). The Choi moiety is present in all aeruginosins as well as the Hpla and phenyllactic acid (Pla) units that are found predominantly in Microcystis and Planktothrix, respectively.…”

A comparative study of the metabolic profiles of common nuisance cyanobacteria in southern perialpine lakes

“…3. This net difference compared to the other species can be related to their remarkable ability to produce different classes of peptidic secondary metabolites (included toxic MCs), as demonstrated by the mass of data available in the literature (Czarnecki et al, 2006;Rounge et al, 2007;Ersmark et al, 2008;Rohrlack et al, 2008;Briand et al, 2016;Spoof et al, 2016). This is confirmed by the fact that, among the 27 peptides reported in Tab.…”

“…1) with those of known compounds. We used online resources (e.g., Norine: http://bioinfo.lifl.fr/NRP/) (Flissi et al, 2016), and literature (Czarnecki et al, 2006;Rounge et al, 2007;Ersmark et al, 2008;Rohrlack et al, 2008;Briand et al, 2016;Spoof et al, 2016) for finding possible matches. We restricted the search in the mass range typical of cyanobacteria peptidic secondary metabolites: aeruginosins (600-700 Da), microginins (700-800 Da), anabaenopeptins (800 -900 Da), microcystins and cyanopeptolins (900-1100 Da).…”