Stabilization of protein-protein interactions in drug discovery

作者：Sebastian A. Andrei, Eline Sijbesma, Michael M. Hann, Jeremy Davis, Gavin O’Mahony, Matthew W. D. Perry, Anna Karawajczyk, Jan Eickhoff, Luc Brunsveld, Richard G. Doveston, L.‐G. Milroy, Christian Ottmann · 发表于：Expert Opinion on Drug Discovery · 年份：2017 · DOI：10.1080/17460441.2017.1346608 · 被引用次数：171 · 研究领域：Peptidase Inhibition and Analysis、Protein Degradation and Inhibitors、Monoclonal and Polyclonal Antibodies Research

INTRODUCTION: PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery. Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing number of synthetic small-molecule PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach. Expert opinion: Both the natural products and the growing number of synthetic molecules show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compound libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of molecules reviewed here in our opinion justify these efforts.