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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Current Frontiers

Targeting Protein-Protein Interaction with Covalent Small-Molecule Inhibitors

Author(s): Bingbing Li, Deqin Rong and Yuanxiang Wang*

Volume 19, Issue 21, 2019

Page: [1872 - 1876] Pages: 5

DOI: 10.2174/1568026619666191011163410


PPIs are involved in diverse biochemical events and perform their functions through the formation of protein-protein complexes or PPI networks. The large and flat interacting surfaces of PPIs make discovery of small-molecule modulators a challenging task. New strategies and more effective chemical technologies are needed to facilitate the development of PPIs small-molecule inhibitors. Covalent modification of a nucleophilic residue located proximally to the immediate vicinity of PPIs can overcome the disadvantages of large interacting surfaces and provides high-affinity inhibitors with increased duration of action and prolonged target modulation. On the other hand, covalent inhibitors that target non-conserved protein residues demonstrate improved selectivity over related protein family members. Herein, we highlight the latest progress of small-molecule covalent PPIs inhibitors and hope to shed light on future PPIs inhibitor design and development. The relevant challenges and opportunities are also discussed.

Keywords: Protein-protein interaction, covalent inhibitor, cysteine, lysine, methionine, GPCR.

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