2. Academic Validation
  3. Noncovalent Peptide Stapling Using Alpha-Methyl-l-Phenylalanine for α-Helical Peptidomimetics

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

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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