Journal article
Optimization of Benzothiazole and Thiazole Hydrazones as Inhibitors of Schistosome BCL-2
W Nguyen, EF Lee, M Evangelista, M Lee, TJ Harris, PM Colman, NA Smith, LB Williams, KE Jarman, KN Lowes, C Haeberli, J Keiser, BJ Smith, WD Fairlie, BE Sleebs
ACS Infectious Diseases | AMER CHEMICAL SOC | Published : 2021
Abstract
Limited therapeutic options are available for the treatment of human schistosomiasis caused by the parasitic Schistosoma flatworm. The B cell lymphoma-2 (BCL-2)-regulated apoptotic cell death pathway in schistosomes was recently characterized and shown to share similarities with the intrinsic apoptosis pathway in humans. Here, we exploit structural differences in the human and schistosome BCL-2 (sBCL-2) pro-survival proteins toward a novel treatment strategy for schistosomiasis. The benzothiazole hydrazone scaffold previously employed to target human BCL-XL was repurposed as a starting point to target sBCL-2. We utilized X-ray structural data to inform optimization and then applied a scaffol..
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Awarded by State Government of Victoria
Funding Acknowledgements
This work was funded by the National Health and Medical Research Council of Australia (Development Grant 1135421 and Project Grant 1143974 to B.E.S.; Project Grant 1002227 to W.D.F; Program Grant 1113133 and Fellowship 1116934 to P.M.C.), the Victorian Cancer Agency Mid-Career Fellowship MCRF9045 to E.F. L., the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. B.E.S. is a Corin Centenary Fellow. J.K. is grateful to the Swiss National Science Foundation for financial support (320030_175585). The authors would like to thank Associate Professor Guillaume Lessene and Dr. Helene Jousset Sabroux for useful discussions.