New MD2 inhibitors derived from curcumin with improved anti-inflammatory activity

European Journal of Medicinal Chemistry
Yali ZhangGuang Liang

Abstract

An overactive Toll-like receptor (TLR) signaling complex is a significant pathogenic factor of acute and chronic inflammatory diseases. The natural product curcumin is reported to inhibit the TLR4 co-receptor, MD2 (myeloid differentiation protein 2), but its low in vivo bioavailability limits its therapeutic potential. We developed new curcumin analogs (MACs) with removal of the β-diketone moiety and substituted residues in benzene rings, and identify these as potential MD2 inhibitors with improved inhibition potency and stability over that of curcumin. Specifically, MAC 17 and 28 showed the highest anti-inflammatory activity, with >90% inhibition of LPS-stimulated cytokine secretion from macrophages, and protected against LPS-induced acute lung injury and sepsis. The MACs inhibited the TLR4-MD2 signaling complex through competition with LPS for binding on MD2, likely at Arg90. Our findings indicated that MAC 17 and 28 are promising candidates for future development as therapeutic drugs for inflammatory diseases with an endotoxin etiology.

Citations

May 17, 2019·Expert Opinion on Drug Discovery·Eirini Chainoglou, Dimitra Hadjipavlou-Litina
Jul 28, 2019·Journal of Cellular and Molecular Medicine·Junying Ding, Qingquan Liu
Aug 21, 2019·Phytotherapy Research : PTR·Arash KarimiAli Tarighat-Esfanjani
Jan 11, 2020·Frontiers in Endocrinology·Saumik BiswasSubrata Chakrabarti
Sep 13, 2019·Nutrients·Laura VollonoElena Campione
Jul 12, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Rossella FioravantiAntonello Mai
Mar 8, 2019·International Journal of Molecular Sciences·Martina BarchittaGuido Basile
Oct 16, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Xubiao WeiManyi Zhang

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