Potent Inhibitors of Pro-Inflammatory Cytokine Production Produced by a Marine-Derived Bacterium

Abstract

Cytokines produced through the Antigen Presenting Cell (APC)-T-cell interaction play a key role in the activation of the allergic asthmatic response. Evaluating small molecules that inhibit the production of these pro-inflammatory proteins is therefore important for the discovery of novel chemical structures with potential anti-asthma activity. We adapted a mouse splenocyte cytokine assay to screen a library of 2,500 marine microbial extracts for their ability to inhibit T H 2 cytokine release and identified potent activity in a marine-derived strain CNQ431, identified as a Streptomyces species. Bioactivity guided fractionation of the organic extract of this strain led to the isolation of ten new 9-membered bis-lactones, splenocins A-J (1-10). The new compounds display potent biological activities, comparable to that of the corticosteroid dexamethasone, with IC 50 values from 2-50 nanomolar in the splenocyte cytokine assay. This study provides the foundation for the optimization of these potent anti-inflammatory compounds for development in the treatment of asthma.

Discovery of Antimycin-Type Depsipeptides from a wbl Gene Mutant Strain of Deepsea-Derived Streptomyces somaliensis SCSIO ZH66 and Their Effects on Pro-inflammatory Cytokine Production

“…Fenical and colleagues reported that splenocins A–J, a subfamily of antimycin-type depsipeptides, exhibited strong inhibition against IL-5 production, some of which are comparable to that of the corticosteroid drug dexamethasone (Strangman et al, 2009). Among them, splenocin B exhibited the strongest inhibition with IC 50 value of 1.8 nM, while splenocin J showed the weakest activity (IC 50 = 1022.7 nM).…”

Marine natural products

“…69 Of the arenamides A-C 5-7 from Salinispora arenicola [sediment, (Great Astrolabe Reef, Fiji)], 5 and 6 blocked tumour necrosis factor (TNF)-induced activation, inhibited nitric oxide and prostaglandin E 2 production and were moderately cytotoxic to HCT-116 cells. 90 95 Culture of another Streptomyces sp. 71 Antiprotealide, described previously as a synthetic compound, 72 was isolated as a natural product from a large-scale fermentation of S. tropica.…”

Nocapyrones H–J, 3,6-Disubstituted α-Pyrones from the Marine Actinomycete <i>Nocardiopsis</i> sp. KMF-001

“…Previously reported literatures demonstrated that the form of alkyl functionalities (e.g., chain length, branch, and attached position) conjugated with aromatic compounds could cause remarkable differences of biological activities. [40][41][42][43] In this case, nocapyrone H, which has a branched alkyl chain, possesses significant neuro-protective effect.…”