title: Pharmaceutical implications of helix length control in helix-mediated protein-protein interactions.
abstract: The most abundant protein secondary structure in nature - the α-helix - is frequently found at protein interfaces, making it an important lead structure for the design of small-molecule modulators of protein-protein interactions (PPIs). Nature's ability to precisely control the length of α-helices, especially in the context of helix-mediated PPIs, is key to ensuring the optimal interaction of protein partners. By extension, precise control over the length of α-helix mimetics is necessary to ensure optimal disruption of α-helix-mediated PPIs. This article will highlight the emerging importance of helix length control in the context of helix-mediated PPIs through a discussion of the contemporary chemical approaches to identifying novel helix mimetic inhibitors, including all-hydrocarbon stapling, hydrogen bond surrogates and optimized peptides emerging from in vitro screening methods. A current update on the therapeutic status of the different approaches is provided, as well as indications as to their long-term potential.
authors.affiliation: Laboratory of Chemical Biology & Institute of Complex Molecular Systems, Department of Biomedical Engineering, Technische Universiteit Eindhoven, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands.
authors.forename: Lech-Gustav
authors.initials: LG
authors.lastname: Milroy
authors.forename: Luc
authors.initials: L
authors.lastname: Brunsveld
mesh_terms: D006860:Hydrogen Bonding; D008958:Models, Molecular; D018716:Molecular Mimicry; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011506:Proteins