A genome-scale drug discovery pipeline uncovers therapeutic targets and a unique p97 allosteric binding site in Schistosoma mansoni

• 成果类型: Article
• 署名作者: Stephens, Dylon R.; Fung, Ho Yee Joyce; Han, Yan; Liang, Jue; Chen, Zhe; Ready, Joseph; Collins, James J.
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Howard Hughes Medical Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13538
• DOI: 10.1073/pnas.2505710122
• 发表日期: 2025-09-02
• 关键词: aaa atpase p97; p97/valosin-containing protein; nucleotide-binding; mat2a inhibitor; praziquantel; solubility; resistance; physiology; mechanism; covalent

摘要

Schistosomes are parasitic flatworms that infect more than 200 million people globally. However, there is a shortage of molecular tools that enable the discovery of potential drug targets within schistosomes. Thus, praziquantel has remained the frontline treatment for schistosomiasis despite known liabilities. Here, we have conducted a genome- wide study in Schistosoma mansoni using the human druggable genome as a bioinformatic template to identify essential genes within schistosomes bearing similarity to catalogued drug targets. Then, we assessed these candidate targets in silico using a set of unbiased criteria to determine which possess ideal characteristics for a ready- made drug discovery campaign. Following this prioritization, we pursued a parasite p97 ortholog as a bona- fide drug target for the development of therapeutics to treat schistosomiasis. From this effort, we identified a covalent inhibitor series that kills schistosomes through an on- target killing mechanism by disrupting the ubiquitin proteasome system. Fascinatingly, these inhibitors induce a conformational change in the conserved D2 domain P- loop of schistosome p97 upon modification of Cys519. This conformational change reveals an allosteric binding site adjacent to the D2 domain active site reminiscent of the DFG flip in protein kinases. This allosteric binding site can potentially be utilized to generate new classes of species- selective p97 inhibitors. Furthermore, these studies provide a resource for the development of alternative therapeutics for schistosomiasis and a workflow to identify potential drug targets in similar systems with few available molecular tools.