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Small Molecule Analogues of the Immunomodulatory Protein, ES-62: Potential Anti-inflammatory Compounds and Mechanism of Action
Colin J. Suckling * 1 , William Harnett 2 , Margaret Harnett 3 , Kamal Saikh 4 , Mark Olson 5
1  WestCHEM Research School, Department of Pure & Applied Chemistry, University of Strathclyde, Glasgow, Scotland
2  Professor of Molecular Immunology, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland
3  Professor of Immune Signalling Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, Scotland.
4  Department of Immunology, Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
5  Department of Cell Biology and Biochemistry, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA

Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3
10.3390/ecmc-3-04644
Abstract:

ES-62, a secreted product of the parasitic filarial nematode, Acanthocheilonema viteae, has been shown in several studies to be a highly effective immunomodulatory agent. It interferes with the pro-inflammatory responses of a number of immune system cells including B cells, dendritic cells (DCs), macrophages and mast cells. Consequently ES-62 has protective effects in a number of mouse models of inflammatory disease, in particular collagen-induced arthritis (CIA), ovalbumin-induced airway-hyper-responsiveness (OAH), oxazolone-induced skin hypersensitivity (OSH), the MRL/Lpr model of systemic lupus erythematosus (SLE), and the Gld.ApoE-/- model of accelerated atherosclerosis in SLE. The biological activity of ES-62 dependens upon post-translational attachment of phosphorylcholine (PC) to an N–type glycan. To obtain potentially beneficial therapeutic effects not accessible to a protein of this type a library of small molecule analogues (SMAs) based upon the active PC moiety but containing chemically stable substitutes for the phosphate ester. Phopshonates, sulfones and sulfonamides were all investigated of which the sulfones were found to have the most immunomodulatory properties. Sulfone containing SMAs have since been found to be effective in treating mouse models of inflammatory diseases noted above. In this paper, potential mechanisms of action including receptor binding and various downstream signalling modifications are considered with the most substantial evidence emerging in favour of blocking essential interactions of the scaffolding protein MyD-88 with its partners thereby reducing the effect of TLR4 activation which in turn leads to a reduction in the release of pro-inflammatory cytokines from the targeted cells.

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