期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 66, 期 7, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/aac.00017-22
关键词
ReFRAME library; Giardia lamblia strains; EGFR tyrosine kinase inhibitors
资金
- Bill & Melinda Gates Foundation [OPP1107194]
- Washington Research Foundation [A154619]
- National Institute of Allergy and Infectious Diseases
- National Institutes of Health [R21AI140881, R56AI146067, R01AI158524]
- Bill and Melinda Gates Foundation [OPP1107194] Funding Source: Bill and Melinda Gates Foundation
A phenotypic screen of the ReFRAME compound library identified Mavelertinib as a potential therapeutic for giardiasis. It showed efficacy against metronidazole-resistant strains and demonstrated good results in a mouse model.
A phenotypic screen of the ReFRAME compound library was performed to identify cell-active inhibitors that could be developed as therapeutics for giardiasis. A primary screen against Giardia lamblia GS clone H7 identified 85 cell-active compounds at a hit rate of 0.72%. A cytotoxicity counterscreen against HEK293T cells was carried out to assess hit compound selectivity for further prioritization. Mavelertinib (PF-06747775), a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), was identified as a potential new therapeutic based on indication, activity, and availability after reconfirmation. Mavelertinib has in vitro efficacy against metronidazole-resistant 713-M3 strains. Other EGFR-TKIs screened in follow-up assays exhibited insignificant inhibition of G. lamblia at 5 mu M, suggesting that the primary molecular target of mavelertinib may have a different mechanistic binding mode from human EGFR-tyrosine kinase. Mavelertinib, dosed as low as 5 mg/kg of body weight or as high as 50 mg/kg, was efficacious in the acute murine Giardia infection model. These results suggest that mavelertinib merits consideration for repurposing and advancement to giardiasis clinical trials while its analogues are further developed.
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