Stabilized helical peptides: overview of the technologies and its impact on drug discovery

ABSTRACT

Introduction: Protein-protein interactions are predominant in the workings of all cells. Until now, there have been a few successes in targeting protein-protein interactions with small molecules. Peptides may overcome some of the challenges of small molecules in disrupting protein-protein interactions. However, peptides present a new set of challenges in drug discovery. Thus, the study of the stabilization of helical peptides has been extensive.

Areas covered: Several technological approaches to helical peptide stabilization have been studied. In this review, stapled peptides, foldamers, and hydrogen bond surrogates are discussed. Issues regarding design principles are also discussed. Furthermore, this review introduces select computational techniques used to aid peptide design and discusses clinical trials of peptides in a more advanced stage of development.

Expert opinion: Stabilized helical peptides hold great promise in a wide array of diseases. However, the field is still relatively new and new design principles are emerging. The possibilities of peptide modification are quite extensive and expanding, so the design of stabilized peptides requires great attention to detail in order to avoid a large number of failed lead peptides. The start of clinical trials with stapled peptides is a promising sign for the future.

KEYWORDS:

• Alpha helix
• beta-peptides
• drug discovery
• foldamers
• hydrogen bond surrogate
• molecular dynamics
• protein-protein interactions
• stapled peptides

Article highlights

• Protein-protein interactions contribute greatly to cell biology and function and are an untapped target for drug discovery.

• Stabilization of helical peptides improve drug-like characteristics of peptides and may be the basis of protein-protein interaction inhibitors as drugs.

• Several techniques have been used to stabilize helical peptides, including hydrocarbon-staples, foldamers, and hydrogen bond surrogates, to name a few.

• Design and development of stabilized helical peptides present challenges that are starting to be overcome.

• Clinical trials of stapled peptides have been initiated. Due to the complex nature and vast size of the chemical space of peptides, many more computational studies should be incorporated into the design and evaluation phases of stabilized helical peptide development.

This box summarizes key points contained in the article.

Declaration of interest

M Klein has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

M Klein is funded by the Minneapolis Veterans Health Care System and this work was supported by Department of Defense (via the Peer-Reviewed Cancer Career Development Award W81XWH-13-1-0372 (CA120102))