Pharmaceutical implications of helix length control in helix-mediated protein-protein interactions

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.