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

Al-Riyami, L., Pineda, M.A. , Rzepecka, J., Huggan, J.K., Khalaf, A.I., Suckling, C.J., Scott, F.J., Rodgers, D.T., Harnett, M.M. and Harnett, W. (2013) 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. Journal of Medicinal Chemistry, 56(24), pp. 9982-10002. (doi:10.1021/jm401251p)

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Abstract

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 on relevant macrophage cytokine responses, a sulfone-containing phosphorylcholine analogue (11a) was selected for testing in an in vivo model of inflammation, 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Harnett, Professor Margaret and Pineda, Dr Miguel
Authors: Al-Riyami, L., Pineda, M.A., Rzepecka, J., Huggan, J.K., Khalaf, A.I., Suckling, C.J., Scott, F.J., Rodgers, D.T., Harnett, M.M., and Harnett, W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Medicinal Chemistry
ISSN:0022-2623
ISSN (Online):1520-4804

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