Bifunctional chemical probes inducing protein-protein interactions

Chiara Maniaci, Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journalReview article

Abstract

Stabilizing biomolecular interactions with synthetic molecules to impact biological function is a concept of enormous appeal. Although much effort has been devoted to disrupting protein-protein interactions (PPIs) using inhibitors, less attention has been directed toward the reverse strategy, that of inducing new PPIs. However recent years have seen a resurgence of interest in designing molecules that bring proteins together. This approach promises to significantly expand the range of tractable targets for chemical biology and therapeutic intervention. Pioneering structural and biophysical investigation of ternary complexes formed by mono- and bifunctional ligands highlight that proximity-induced stabilization or de novo formation of PPIs are a common feature of their molecular recognition. In this review, we illustrate these concepts and advances with representative case studies, and highlight progress over the past three years, with particular focus on recruitment to E3 ubiquitin ligases by “molecular glues” and chimeric dimerizers (PROTACs) for targeted protein degradation.
Original languageEnglish
Pages (from-to)145-156
Number of pages12
JournalCurrent Opinion in Chemical Biology
Volume52
Early online date13 Aug 2019
DOIs
Publication statusPublished - Oct 2019

Fingerprint

Proteins
Ubiquitin-Protein Ligases
Molecules
Glues
Adhesives
Proteolysis
Ligands
Stabilization
Degradation
Therapeutics

Keywords

  • Protein-protein interactions
  • molecular glues
  • chemical inducers of dimerization
  • chimeric molecules
  • PROTACs
  • ternary complexes

Cite this

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title = "Bifunctional chemical probes inducing protein-protein interactions",
abstract = "Stabilizing biomolecular interactions with synthetic molecules to impact biological function is a concept of enormous appeal. Although much effort has been devoted to disrupting protein-protein interactions (PPIs) using inhibitors, less attention has been directed toward the reverse strategy, that of inducing new PPIs. However recent years have seen a resurgence of interest in designing molecules that bring proteins together. This approach promises to significantly expand the range of tractable targets for chemical biology and therapeutic intervention. Pioneering structural and biophysical investigation of ternary complexes formed by mono- and bifunctional ligands highlight that proximity-induced stabilization or de novo formation of PPIs are a common feature of their molecular recognition. In this review, we illustrate these concepts and advances with representative case studies, and highlight progress over the past three years, with particular focus on recruitment to E3 ubiquitin ligases by “molecular glues” and chimeric dimerizers (PROTACs) for targeted protein degradation.",
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author = "Chiara Maniaci and Alessio Ciulli",
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Bifunctional chemical probes inducing protein-protein interactions. / Maniaci, Chiara; Ciulli, Alessio (Lead / Corresponding author).

In: Current Opinion in Chemical Biology, Vol. 52, 10.2019, p. 145-156.

Research output: Contribution to journalReview article

TY - JOUR

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AU - Ciulli, Alessio

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PY - 2019/10

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