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Eur J Med Chem. 2018 Mar 25;148:291-305. doi: 10.1016/j.ejmech.2018.02.008. Epub 2018 Feb 15.

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

Author information

1
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Pharmacy, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
2
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
3
Department of Pharmacy, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
4
The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China. Electronic address: szzhanghong126@126.com.
5
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Pharmacy, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: wzmcliangguang@163.com.

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.

KEYWORDS:

Acute lung injury; Curcumin; Inflammation; MD2; Sepsis

PMID:
29466778
DOI:
10.1016/j.ejmech.2018.02.008
[Indexed for MEDLINE]

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