Noncovalent Peptide Stapling Using Alpha-Methyl-l-Phenylalanine for α-Helical Peptidomimetics

  • J Am Chem Soc. 2023 Sep 20;145(37):20242-20247. doi: 10.1021/jacs.3c02743.
Ross A D Bathgate  1  2 ,  Praveen Praveen  1 ,  Ashish Sethi  2  3 ,  Werner I Furuya  1 ,  Rishi R Dhingra  1  4 ,  Martina Kocan  1 ,  Qinghao Ou  1 ,  Adam L Valkovic  1 ,  Isis Gil-Miravet  5 ,  Mónica Navarro-Sánchez  5 ,  Francisco E Olucha-Bordonau  5 ,  Andrew L Gundlach  1  4  6 ,  K Johan Rosengren  7 ,  Paul R Gooley  2  8 ,  Mathias Dutschmann  1  4 ,  Mohammed Akhter Hossain  1  4  9
Affiliations
  • 1. The Florey, The University of Melbourne, Parkville, VIC 3052, Australia.
  • 2. Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC 3052, Australia.
  • 3. Australian Nuclear Science Technology Organisation, The Australian Synchrotron, Clayton, VIC 3168, Australia.
  • 4. Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3052, Australia.
  • 5. Predepartmental Unit of Medicine, Faculty of Health Sciences, Universitat Jaume I, Avenida de Vicent Sos Baynat, s/n, 12071 Castelló de La Plana, Spain.
  • 6. Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC 3052, Australia.
  • 7. School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia.
  • 8. Bio21 Molecular Science and Biotechnology, The University of Melbourne, Parkville, VIC 3052, Australia.
  • 9. School of Chemistry, The University of Melbourne, Parkville, VIC 3052, Australia.
PMID: 37439676 DOI: 10.1021/jacs.3c02743
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.

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