Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), B-1200 Brussels, Belgium; Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), B-1200 Brussels, Belgium.
Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), B-1200 Brussels, Belgium.
Drug Discov Today. 2021 May;26(5):1148-1163. doi: 10.1016/j.drudis.2021.01.028. Epub 2021 Feb 3.
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.
蛋白质自组装是一种普遍存在的现象，对于稳定性和分子识别至关重要。破坏组成性同型二聚体是药物设计中的一种新颖而新兴的策略。通过直接破坏复合物、亚基插入或促进无活性寡聚状态，可以抑制同型二聚体蛋白。与活性位点抑制相比，靶向自相互作用具有几个优势，因为它可以刺激蛋白质降解、提高选择性、亚化学计量抑制，并绕过补偿机制。这种蛋白质抑制的新领域是由适合研究同型二聚体的生物物理和生化工具的发展所驱动的，如差示扫描荧光法（DSF）、天然质谱法（MS）、荧光共振能量转移（FRET）光谱法、二维核磁共振（NMR）和 X 射线晶体学。在这篇综述中，我们讨论了药物设计这一新范例的不同方面。
