Design, synthesis and biological evaluation of dipeptides as novel non-covalent 20S proteasome inhibitors

• Published in: Journal of asian natural products research Vol. 23; no. 5; pp. 436 - 451
• Main Authors: Yang, Ya-Jun, Wang, Ke, Yang, Ying, Lai, Fang-Fang, Chen, Xiao-Guang, Xiao, Zhi-Yan
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 04.05.2021; Taylor & Francis Ltd
• Subjects: 20S proteasome inhibitors; Caspase; Chemistry; Chemistry, Applied; Chemistry, Medicinal; Chymotrypsin; dipeptides; Dipeptides - pharmacology; Inhibitors; Life Sciences & Biomedicine; Molecular Structure; non-covalent; Pharmacology & Pharmacy; Physical Sciences; Plant Sciences; Proteasome Endopeptidase Complex - metabolism; Proteasome inhibitors; Proteasome Inhibitors - pharmacology; Science & Technology; Trypsin; non-covalent; 20S proteasome inhibitors; dipeptides
• ISSN: 1028-6020; 1477-2213
• DOI: 10.1080/10286020.2021.1910241

Based on the interaction modes of the natural 20S proteasome inhibitors TMC-95A, we have previously discovered a dipeptide 1. To explore the SAR around compound 1, we designed and synthesized a series of dipeptides (8-38) with a fragment-based strategy. Among them, nine compounds showed significant inhibitory activities against the chymotrypsin-like activity of human 20S proteasome with IC 50 values at the submicromolar level, which were comparable or even superior to the parent compound 1. Meanwhile, they displayed no significant inhibition against trypsin-like and caspase-like activities of 20S proteasome. The results suggested the feasibility to design dipeptides as novel and potent 20S proteasome inhibitors.