Fungal- derived methyldeoxaphomins target Plasmodium falciparum segregation through the inhibition of PfActin1
成果类型：
Article
署名作者：
Jiang, Tiantian; Lee, Jin Woo; Collins, Jennifer E.; Schaefer, Samuel; Chen, Daisy; Nardella, Flore; Wendt, Karen; Peramuna, Thilini G.; Paes, Raphaella; Mclellan, James L.; Bhasin, Jasveen; Durst, Gregory L.; Hanson, Kirsten K.; Chakrabarti, Debopam; Cichewicz, Robert H.; Winzeler, Elizabeth A.
署名单位：
University of California System; University of California San Diego; Duksung Women's University; State University System of Florida; University of Central Florida; University of Michigan System; University of Michigan; University of Texas System; University of Texas at San Antonio; University of California System; University of California San Diego
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-15062
DOI：
10.1073/pnas.2418871122
发表日期：
2025-02-25
关键词：
摘要：
Herein we report the finding and structure determination of a natural product based on the methyldeoxaphomin scaffold family from the fungus Trichocladium asperum that shows promising antiplasmodial activity and selectivity against host cells. In vitro evolution and whole genome analysis in Plasmodium falciparum with shows that parasite resistance to methyldeoxaphomins is strongly associated with mutations in PfActin1 (PF3D7_1246200), a critically essential ATPase needed for all stages of parasite development. Molecular docking study with available PfActin1 crystal structure shows NPDG- F occupies the same allosteric binding pocket as in the allosteric site was supported by cross- resistance studies, isobologram analysis with other PfActin1 inhibitors, and the structure-activity relationships for the morphological abnormalities in merozoite cellularization during schizogony in both PfActin1 is an attractive, pan- lifecycle target and inform strategies for the design of more selective inhibitors.