Targeting protein self-association in drug design. Issue 5 (May 2021)

• Record Type: Journal Article
• Authors: Thabault, Léopold; Liberelle, Maxime; Frédérick, Raphaël
• Is Part Of: Drug discovery today. Volume 26:Issue 5(2021)
• Page Start: 1148
• Page End: 1163
• Publication Date: 2021-05
• Subjects: Drugs -- Design -- Periodicals; Drugs -- Research -- Periodicals; 615.1
• DOI: 10.1016/j.drudis.2021.01.028
• Languages: English
• ISSNs: 1359-6446

Abstract

Graphical abstract: Highlights: Homomeric interfaces are a pool of potential allosteric sites for challenging targets. Homomeric disruption can lead to target degradation and sub-stoichiometric inhibition. Targeting homomeric interfaces can provide more specific inhibitors. Targeting self-association can lead to several original mechanisms of inhibition. Abstract : Protein self-association is a universal phenomenon essential for stability and molecular recognition. Disrupting constitutive homomers constitutes an original and emerging strategy in drug design. Inhibition of homomeric proteins can be achieved through direct complex disruption, subunit intercalation, or by promoting inactive oligomeric states. Targeting self-interaction grants several advantages over active site inhibition because of the stimulation of protein degradation, the enhancement of selectivity, substoichiometric inhibition, and by-pass of compensatory mechanisms. This new landscape in protein inhibition is driven by the development of biophysical and biochemical tools suited for the study of homomeric proteins, such as differential scanning fluorimetry (DSF), native mass spectrometry (MS), Förster resonance energy transfer (FRET) spectroscopy, 2D nuclear magnetic resonance (NMR), and X-ray crystallography. In this review, we discuss the different aspects of this new paradigm in drug design. Teaser: Disrupting protein self-association bears great therapeutic promises and could provide exciting alternatives to active-site inhibitors.