CryoEM Structure with ATP Synthase Enables Late‐Stage Diversification of Cruentaren A-Reference-Cited by-同舟云学术

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

Published:2023-04-13 Issue:29 Volume:29 Page:
ISSN:0947-6539
Container-title:Chemistry – A European Journal
language:en
Short-container-title:Chemistry A European J

Author:

Dou Xiaozheng¹,Guo Hui²³,D'Amico Terin¹,Abdallah Leah⁴,Subramanian Chitra⁵,Patel Bhargav A.¹,Cohen Mark⁵,Rubinstein John L.²³⁶,Blagg Brian S. J.¹^ORCID

Affiliation:

1. Department of Chemistry and Biochemistry The University of Notre Dame Notre Dame IN 46556 USA

2. Molecular Medicine Program The Hospital for Sick Children Toronto ON M5G 0A4 Canada

3. Department of Medical Biophysics University of Toronto Toronto ON M5G 1L7 Canada

4. Department of Surgery University of Michigan Ann Arbor MI 48109 USA

5. Departments of Surgery and Bioengineering Carle Illinois College of Medicine University of Illinois Urbana-Champaign IL 61801 USA

6. Departments of Biochemistry University of Toronto Toronto ON M5S 1A8 Canada

Abstract

AbstractCruentaren 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.

Funder

Center for Scientific Review

Publisher

Wiley

Subject

General Chemistry,Catalysis,Organic Chemistry

Link

https://onlinelibrary.wiley.com/doi/pdf/10.1002/chem.202300262

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