Noncovalent Peptide Stapling Using Alpha-Methyl-<scp>l</scp>-Phenylalanine for α-Helical Peptidomimetics
Ross A. D. Bathgate, Praveen Praveen, Ashish Sethi, Werner I. Furuya, Rishi R. Dhingra, Martina Kočan, Qinghao Ou, Adam L. Valkovic, Isis Gil‐Miravet, Mónica Navarro-Sánchez, Francisco E. Olucha‐Bordonau, Andrew L. Gundlach, K. Johan Rosengren, Paul R. Gooley, Mathias Dutschmann, Mohammed Akhter Hossain
Abstract
Peptides and peptidomimetics are attractive drug candidates because of their high target specificity and low-toxicity profiles. Developing peptidomimetics using hydrocarbon (HC)-stapling or other stapling strategies has gained momentum because of their high stability and resistance to proteases; however, they have limitations. Here, we take advantage of the α-methyl group and an aromatic phenyl ring in a unique unnatural amino acid, α-methyl- l -phenylalanine (αF), and propose a novel, noncovalent stapling strategy to stabilize peptides. We utilized this strategy to create an α-helical B-chain mimetic of a complex insulin-like peptide, human relaxin-3 (H3 relaxin). Our comprehensive data set ( in vitro, ex vivo, and in vivo ) confirmed that the new high-yielding B-chain mimetic, H3B10-27(13/17αF), is remarkably stable in serum and fully mimics the biological function of H3 relaxin. H3B10-27(13/17αF) is an excellent scaffold for further development as a drug lead and an important tool to decipher the physiological functions of the neuropeptide G protein-coupled receptor, RXFP3.