A designed cyclic peptide based on Trastuzumab used to construct peptide-drug conjugates for its HER2-targeting ability

Jiaqi Zhou; Yuxing Zou; Yan Cai; Fanglian Chi; Wenlong Huang; Wei Shi; Hai Qian

doi:10.1016/j.bioorg.2021.105453

A designed cyclic peptide based on Trastuzumab used to construct peptide-drug conjugates for its HER2-targeting ability

Bioorg Chem. 2021 Dec:117:105453. doi: 10.1016/j.bioorg.2021.105453. Epub 2021 Oct 26.

Authors

Jiaqi Zhou¹, Yuxing Zou¹, Yan Cai¹, Fanglian Chi¹, Wenlong Huang², Wei Shi³, Hai Qian⁴

Affiliations

¹ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
² Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
³ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: shiwei@cpu.edu.cn.
⁴ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: qianhai24@163.com.

PMID: 34736138
DOI: 10.1016/j.bioorg.2021.105453

Abstract

Human epidermal growth factor receptor 2 (HER2) has been recognized as an important therapeutic target for its overexpression in many cancers. Trastuzumab is a monoclonal antibody targeting HER2, which has been approved by FDA to treat HER2-positive cancer. In this research, cyclic peptide Cyclo-GCGPep1 was designed based on the binding mode between antibody and HER2 protein in silico, which has been confirmed possessing good affinity with HER2. Cyclo-GCGPep1 was also used to construct peptide-drug conjugates with Camptothecin. Biological evaluations demonstrated that Conjugate 1 has a good antiproliferative activity on SK-BR-3 and NCI-N87 cells. Conjugate 1 retained the pro-apoptotic and Topo I inhibitory ability of Camptothecin. Meanwhile, it has good targeting ability towards HER2-positive cells with the help of Cyclo-GCGPep1. It also has better permeability in the tumor spheroid model than Camptothecin. In summary, the design of cyclic peptide derived from antibody is of significance for the discovery of targeting peptides and Conjugate 1 is expected as a good therapeutic agent for HER2-positive cancers.

Keywords: Cyclic peptides; HER2; Peptide-drug conjugates; Trastuzumab.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Peptides, Cyclic / chemical synthesis
Peptides, Cyclic / chemistry
Peptides, Cyclic / pharmacology*
Receptor, ErbB-2 / antagonists & inhibitors*
Receptor, ErbB-2 / metabolism
Structure-Activity Relationship
Trastuzumab / chemistry
Trastuzumab / pharmacology*

Substances

Antineoplastic Agents
Peptides, Cyclic
ERBB2 protein, human
Receptor, ErbB-2
Trastuzumab