Rational design of peptide inhibitors targeting HSP90–CDC37 protein–protein interaction

Author:

Zhang Qiuyue12ORCID,Yan Ling12,Zhang Yuxuan12,Zhang Lixiao12,Yu Jia12,You Qidong12ORCID,Wang Lei12ORCID

Affiliation:

1. State Key Laboratory of Natural Medicines & Jiangsu Key Laboratory of Drug Design & Optimization, China Pharmaceutical University, Nanjing, 210009, China

2. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China

Abstract

Background: Specifically blocking HSP90–CDC37 interaction is emerging as a prospective strategy for cancer therapy. Aim: Applying a kinase pseudopeptide rationale to the discovery of HSP90–CDC37 protein–protein interaction (PPI) inhibitors. Methods: Pseudosubstrates were identified through sequence alignment and evaluated by biolayer interferometry assay, co-immunoprecipitation assay and antiproliferation assay. Results: TAT-DDO-59120 was identified to disrupt HSP90–CDC37 PPI through directly binding to HSP90, both extracellularly and intracellularly. In addition, the identified peptide showed ideal antiproliferative activity against the colorectal cancer cell HCT116 (IC50 = 12.82 μM). Conclusion: Compared with the traditional method of screening a large compound library to identify PPI inhibitors, this method is rapid and efficient with strong purpose, which provides a novel strategy for designing HSP90–CDC37 PPI inhibitors.

Funder

Natural Science Foundation of Jiangsu Province

National Natural Science Foundation of China

Publisher

Future Science Ltd

Subject

Drug Discovery,Pharmacology,Molecular Medicine

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