Designing Anti-inflammatory Drugs from Parasitic Worms: A Synthetic Small Molecule Analogue of the Acanthocheilonema viteae Product ES-62 Prevents Development of Collagen-Induced Arthritis

作者：Al Riyami Lamyaa; Pineda Miguel A; Rzepecka Justyna; Huggan Judith K; Khalaf Abedawn I; Suckling Colin J; Scott Fraser J; Rodgers David T; Harnett Margaret M; Harnett William^*

来源：Journal of Medicinal Chemistry, 2013, 56(24): 9982-10002.

DOI：10.1021/jm401251p

In spite of increasing evidence that parasitic worms may protect humans from developing allergic and autoimmune diseases and the continuing identification of defined helminth-derived immunomodulatory molecules, to date no new anti-inflammatory drugs have been developed from these organisms. We have approached this matter in a novel manner by synthesizing a library of drug-like small molecules based upon phosphorylcholine, the active moiety of the anti-inflammatory Acanthocheilonema viteae product, ES-62, which as an immunogenic protein is unsuitable for use as a drug. Following preliminary in vitro screening for inhibitory effects responses, a sulfone-containing phosphorylcholine analogue (11a) was selected for testing in collagen-induced arthritis (CIA). Testing revealed that 11a was as effective as ES-62 in protecting DBA/1 mice from developing CIA and mirrored its mechanism of action in downregulating the TLR/IL-1R transducer, MyD88. 11a is thus a novel prototype for anti-inflammatory drug development. on relevant macrophage cytokine an in vivo model of inflammation,

• 出版日期2013-12-26