Journal article
Noncovalent Peptide Stapling Using Alpha-Methyl-l-Phenylalanine for α-Helical Peptidomimetics
RAD Bathgate, P Praveen, A Sethi, WI Furuya, RR Dhingra, M Kocan, Q Ou, AL Valkovic, I Gil-Miravet, M Navarro-Sánchez, FE Olucha-Bordonau, AL Gundlach, KJ Rosengren, PR Gooley, M Dutschmann, MA Hossain
Journal of the American Chemical Society | AMER CHEMICAL SOC | Published : 2023
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 (..
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Grants
Awarded by Ministerio de Ciencia, Innovación y Universidades
Funding Acknowledgements
This research was funded by NHMRC (Australia) Ideas Grants 1182996 and 2001278 to MAH, 1165801 to KJR and RABD, and 2001027 to RADB and PRG. RADB was supported by an NHMRC Fellowship 1042650. FEOB, IGM, and MNS were supported by Spanish Ministerio de Ciencia, Innovacion y Universidades, grant number RTI2018-095698-B-I00. IGM was supported by fellowship UJI POSDOC/2021/19 (IG-M); MNS was supported by UJI Predoctoral Program PREDOC/2021/19. The authors thank Tania Ferraro and Sharon Layfield for their assistance with biochemical assays and Victoria Ibanez from the statistics department UJI. Studies at The Florey were supported by the Victorian Government's Operational Infrastructure Support Program.