CryoEM Structure with ATP Synthase Enables Late-Stage Diversification of Cruentaren A

Xiaozheng Dou, Hui Guo, Terin D'Amico, Leah Abdallah, Chitra Subramanian, Bhargav A. Patel, Mark Cohen, John L. Rubinstein, Brian S.J. Blagg

Research output: Contribution to journalArticlepeer-review

Abstract

Cruentaren A is a natural product that exhibits potent antiproliferative activity against various cancer cell lines, yet its binding site within ATP synthase remained unknown, thus limiting the development of improved analogues as anticancer agents. Herein, we report the cryogenic electron microscopy (cryoEM) structure of cruentaren A bound to ATP synthase, which allowed the design of new inhibitors through semisynthetic modification. Examples of cruentaren A derivatives include a trans-alkene isomer, which was found to exhibit similar activity to cruentaren A against three cancer cell lines as well as several other analogues that retained potent inhibitory activity. Together, these studies provide a foundation for the generation of cruentaren A derivatives as potential therapeutics for the treatment of cancer.

Original languageEnglish (US)
Article numbere202300262
JournalChemistry - A European Journal
Volume29
Issue number29
DOIs
StatePublished - May 22 2023

Keywords

  • ATP synthase
  • cruentaren A
  • cryoEM structure
  • late-stage modification
  • natural product

ASJC Scopus subject areas

  • General Chemistry
  • Catalysis
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'CryoEM Structure with ATP Synthase Enables Late-Stage Diversification of Cruentaren A'. Together they form a unique fingerprint.

Cite this