Molecular glues modulate protein functions by inducing protein aggregation: A promising therapeutic strategy of small molecules for disease treatment.
10.1016/j.apsb.2022.03.019
- Author:
Hongyu WU
1
;
Hong YAO
1
;
Chen HE
1
;
Yilin JIA
1
;
Zheying ZHU
2
;
Shengtao XU
1
;
Dahong LI
3
;
Jinyi XU
1
Author Information
1. State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
2. Division of Molecular Therapeutics & Formulation, School of Pharmacy, the University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK.
3. Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
- Publication Type:Review
- Keywords:
Dimerization;
Molecular glue;
Polymerization;
Protein–protein interaction;
Small molecule
- From:
Acta Pharmaceutica Sinica B
2022;12(9):3548-3566
- CountryChina
- Language:English
-
Abstract:
Molecular glues can specifically induce aggregation between two or more proteins to modulate biological functions. In recent years, molecular glues have been widely used as protein degraders. In addition, however, molecular glues play a variety of vital roles, such as complex stabilization, interactome modulation and transporter inhibition, enabling challenging therapeutic targets to be druggable and offering an exciting novel approach for drug discovery. Since most molecular glues are identified serendipitously, exploration of their systematic discovery and rational design are important. In this review, representative examples of molecular glues with various physiological functions are divided into those mediating homo-dimerization, homo-polymerization and hetero-dimerization according to their aggregation modes, and we attempt to elucidate their mechanisms of action. In particular, we aim to highlight some biochemical techniques typically exploited within these representative studies and classify them in terms of three stages of molecular glue development: starting point, optimization and identification.
