Stabilization of protein-protein interactions in drug discovery

S.A. Andrei, E. Sijbesma, M. Hann, J. Davis, G. O’Mahony, M.W.D. Perry, A. Karawajczyk, J.E. Eickhoff, L. Brunsveld, R.G. Doveston, L.G. Milroy, C. Ottmann

Research output: Contribution to journalArticleAcademicpeer-review

63 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Pages (from-to)925-940
Number of pages16
JournalExpert Opinion on Drug Discovery
Volume12
Issue number9
DOIs
Publication statusPublished - 2 Sep 2017

Keywords

  • Chemical biology
  • druggable genome
  • medicinal chemistry
  • PPI stabilization
  • PPIs
  • small molecules
  • tool compounds
  • X-ray crystallography
  • Proteins/metabolism
  • Pharmaceutical Preparations/chemical synthesis
  • Drug Discovery/methods
  • Humans
  • Small Molecule Libraries
  • Drug Design
  • Protein Binding
  • Protein Stability
  • Biological Products/pharmacology

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