Lead optimisation efforts on a molecular prototype of the immunomodulatory parasitic protein ES-62

The immunomodulatory property of some parasitic helminths is well documented. The glycoprotein ES-62 from the nematode, acanthocheilonema viteae has been found to possess immunomodulatory properties. Two small molecule analogues (SMA's) of ES-62 (S3 and S5) were found to mimic its immunomodulatory properties in vivo and were active in animal models of allergic, inflammatory and autoimmune diseases. In this work, new efforts were made to further optimise the activities of compound S3 by making small but directed structural changes. A variety of analogues based on the S3 prototype were simulated by making variations at one position and then screened in silico. The best compounds were selected based on predicted physiochemical properties and medicinal chemistry indices and synthesised. Structural elucidation was done via HNMR, LCMS, FTIR and HRESIMS. The predicted properties were evaluated by HPLC method. A total of 11 novel molecules were synthesised and characterised. Significant correlation was obtained between the predicted physicochemical properties and their HPLC retention times (RT) for eight of our novel compounds. This suggests that these compounds may behave in a physiological environment as closely as computationally predicted. This entails, lesser host toxicity while maintaining good or better activities compared to the earlier prototype. They hence provide a good opportunity for development of drugs for immune conditions such as asthma, inflammation and autoimmune diseases.