Protein-protein interactions (PPI) are promiscuous in many biological pathways and their dysfunction is related to several pathologies. Therefore, PPI modulators are not only important probes to understand biological processes, but potential agents for pharmaceutical intervention. Taking into account the high incidence of α–helices within therapeutically relevant PPI interfaces, the big efforts devoted to develop α–helix mimetics is not surprising. In recent years, these effort have been mainly related, on one hand, to the development of synthetic methods for central scaffolds that allow the preparation of libraries and, on the other hand, to the appropriate decoration of known mimetic systems to modulate specific PPI. In addition, α–helix inducers, like those provided by stapled and HBS strategies, and the design of new helical foldamers have been successfully applied to target different PPI both in vitro and in vivo. Although significant achievements have been made, the design of non-peptide scaffolds able to bear more than three amino acid side-chains/surrogates for mimicking more than one helix faces, as well as the effective production of α–helix mimetic libraries, is still open to further progress. It is estimated that more than 30.000 PPI could be therapeutic targets, and many of them have an α–helix hot-spot, so lots of opportunities are awaiting.
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Contributed by Rosario González-Muñiz
Rosario is a Senior Researcher at the Medicinal Chemistry Institute (IQM-CSIC), Madrid. She is involved in peptides, secondary structure mimics and small-molecule peptidomimetics of application in biological/medicinal chemistry programs, especially related to the modulation of ion channels and associated proteins.