Synthetic analogues of the parasitic worm product ES-62 reduce disease development in in vivo models of lung fibrosis

Suckling, Colin J. and Mukherjee, Sambuddho and Khalaf, Abedawn I. and Narayan, Ashwini and Scott, Fraser J. and Khare, Sonal and Dhakshinamoorthy, Saravanakumar and Harnett, Margaret M. and Harnett, William (2018) Synthetic analogues of the parasitic worm product ES-62 reduce disease development in in vivo models of lung fibrosis. Acta Tropica, 185. pp. 212-218. ISSN 0001-706X

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    Abstract

    Parasitic worms are receiving much attention as a potential new therapeutic approach to treating autoimmune and allergic conditions but concerns remain regarding their safety. As an alternative strategy, we have focused on the use of defined parasitic worm products and recently taken this one step further by designing drug-like small molecule analogues of one such product, ES-62, which is anti-inflammatory by virtue of covalently attached phosphorylcholine moieties. Previously, we have shown that ES-62 mimics are efficacious in protecting against disease in mouse models of rheumatoid arthritis, systemic lupus erythematosus and skin and lung allergy. Given the potential role of chronic inflammation in fibrosis, in the present study we have focused our attention on lung fibrosis, a debilitating condition for which there is no cure and which in spite of treatment slowly gets worse over time. Two mouse models of fibrosis - bleomycin-induced and LPS-induced - in which roles for inflammation have been implicated were adopted. Four ES-62 analogues were tested – 11a and 12b, previously shown to be active in mouse models of allergic and autoimmune disease and 16b and AIK-29/62 both of which are structurally related to 11a. All four compounds were found to significantly reduce disease development in both fibrosis models, as shown by histopathological analysis of lung tissue, indicating their potential as treatments for this condition.