Journal article

Optimization of Benzothiazole and Thiazole Hydrazones as Inhibitors of Schistosome BCL-2.

William Nguyen, Erinna F Lee, Marco Evangelista, Mihwa Lee, Tiffany J Harris, Peter M Colman, Nicholas A Smith, Luke B Williams, Kate E Jarman, Kym N Lowes, Cécile Haeberli, Jennifer Keiser, Brian J Smith, W Douglas Fairlie, Brad E Sleebs

ACS Infectious Diseases | 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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