Side‐Chain Engineering Guides the Design of β‐Sheet Inhibitor to Anchor Protein‐Protein Interaction Interfaces
Abstract
Abstract Customizing inhibitors for β‐sheet mediated protein‐protein interactions (PPIs) remains a challenge in medicinal chemistry research. Directly separating β‐sheet elements from the PPI interface as inhibitors represents a feasible strategy. Although useful, peptides derived from PPIs typically lose their natural secondary structure, resulting in low affinity. How to construct stable β‐sheet inhibitors remains elusive, mainly due to the lack of reliable strategies to guide the design of β‐sheet backbones. In this study, we propose an amino acid side‐chain engineering strategy (AASE) to design of β‐sheet inhibitors. Specifically, this strategy was based on the amino acid pairing (AAP) principle observed in the β‐sheets of natural proteins, and further integrates the complementarity of various non‐covalent interactions between β‐strand side chains. When combined with high‐throughput peptide screening technology, above strategy can generate structurally defined β‐sheet inhibitors. We validated the physicochemical properties of the β‐sheet structures obtained under the aforementioned strategy and prioritized the peptide EH. The β‐sheet inhibitor formed by EH exhibits potent biological functions, enabling high‐resolution imaging of tumors in the NIR window and guiding tumor resection. In addition, EH can inhibit tumor growth as a PD‐1/PD‐L1 checkpoint blockade. This strategy provides valuable guidance for the design of PPI inhibitors with β‐sheet structures.
Article Details
Authors (20)
Limin Zhang
Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Center for Quantum Technology Research and School of Physics
Minxuan Wang
Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering Ministry of Industry and Information Technology Key Laboratory of Cluster Science of Ministry of Education Beijing Key Laboratory of Photoelectronic/Electro‐photonic Conversion Materials School of Chemistry and Chemical Engineering Tangshan Research Institute Beijing Institute of Technology Beijing 100081 P.R. China
Bo Wang
Jinge Zhao
Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Center for Quantum Technology Research and School of Physics
Beilei Sun
Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Center for Quantum Technology Research and School of Physics
Yao Yu
Kai Han
Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Center for Quantum Technology Research and School of Physics
Xin Wang
Jian Zhang
Mingshan Wei
Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering Ministry of Industry and Information Technology Key Laboratory of Cluster Science of Ministry of Education Beijing Key Laboratory of Photoelectronic/Electro‐photonic Conversion Materials School of Chemistry and Chemical Engineering Tangshan Research Institute Beijing Institute of Technology Beijing 100081 P.R. China
Jingrui Deng
Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering Ministry of Industry and Information Technology Key Laboratory of Cluster Science of Ministry of Education Beijing Key Laboratory of Photoelectronic/Electro‐photonic Conversion Materials School of Chemistry and Chemical Engineering Tangshan Research Institute Beijing Institute of Technology Beijing 100081 P.R. China
Jie Li
Mengzhen Li
College of Chemistry and Materials
Yubin Ke
China Spallation Neutron Source
Hanqiu Jiang
China Spallation Neutron Source Dongguan 523803 P.R. China
Han Yan
Xiaoyuan Chen
Xubiao Peng
Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Center for Quantum Technology Research and School of Physics
Yu Bai
Weizhi Wang
Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Center for Quantum Technology Research and School of Physics