Biochemistry and Pharmacology - Research Publications

Permanent URI for this collection

Now showing 1 - 1 of 1

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

Bathgate, RAD ; Praveen, P ; Sethi, A ; Furuya, WI ; Dhingra, RR ; Kocan, M ; Ou, Q ; Valkovic, AL ; Gil-Miravet, I ; Navarro-Sanchez, M ; Olucha-Bordonau, FE ; Gundlach, AL ; Rosengren, KJ ; Gooley, PR ; Dutschmann, M ; Hossain, MA (AMER CHEMICAL SOC, 2023-07-13)

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.