Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 145, Issue 37, Pages 20242-20247Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.3c02743
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Researchers have developed a novel noncovalent stapling strategy using an unnatural amino acid called & alpha;-methyl-l-phenylalanine (& alpha;F) to stabilize peptides. They successfully created a peptide mimetic of human relaxin-3 (H3 relaxin) with high stability and biological function similar to H3 relaxin. This peptide mimetic, H3B10-27(13/17 & alpha;F), holds great potential as a drug lead and as a tool for studying the physiological functions of RXFP3.
Peptides and peptidomimetics are attractive drug candidatesbecauseof their high target specificity and low-toxicity profiles. Developingpeptidomimetics using hydrocarbon (HC)-stapling or other staplingstrategies has gained momentum because of their high stability andresistance to proteases; however, they have limitations. Here, wetake advantage of the & alpha;-methyl group and an aromatic phenylring in a unique unnatural amino acid, & alpha;-methyl-l-phenylalanine(& alpha;F), and propose a novel, noncovalent stapling strategy tostabilize peptides. We utilized this strategy to create an & alpha;-helicalB-chain mimetic of a complex insulin-like peptide, human relaxin-3(H3 relaxin). Our comprehensive data set (in vitro, ex vivo, and in vivo) confirmedthat the new high-yielding B-chain mimetic, H3B10-27(13/17 & alpha;F),is remarkably stable in serum and fully mimics the biological functionof H3 relaxin. H3B10-27(13/17 & alpha;F) is an excellent scaffold forfurther development as a drug lead and an important tool to decipherthe physiological functions of the neuropeptide G protein-coupledreceptor, RXFP3.
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