| Autor: |
Levine PM; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington 98195, United States., Craven TW; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington 98195, United States., Li X; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington 98195, United States., Balana AT, Bird GH, Godes M, Salveson PJ; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington 98195, United States., Erickson PW; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington 98195, United States., Lamb M; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington 98195, United States., Ahlrichs M; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington 98195, United States., Murphy M; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington 98195, United States., Ogohara C; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington 98195, United States., Said MY; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington 98195, United States., Walensky LD, Pratt MR, Baker D; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington 98195, United States. |
| Abstrakt: |
Peptide and protein bioconjugation technologies have revolutionized our ability to site-specifically or chemoselectively install a variety of functional groups for applications in chemical biology and medicine, including the enhancement of bioavailability. Here, we introduce a site-specific bioconjugation strategy inspired by chemical ligation at serine that relies on a noncanonical amino acid containing a 1-amino-2-hydroxy functional group and a salicylaldehyde ester. More specifically, we harness this technology to generate analogues of glucagon-like peptide-1 that resemble Semaglutide, a long-lasting blockbuster drug currently used in the clinic to regulate glucose levels in the blood. We identify peptides that are more potent than unmodified peptide and equipotent to Semaglutide in a cell-based activation assay, improve the stability in human serum, and increase glucose disposal efficiency in vivo. This approach demonstrates the potential of "serine ligation" for various applications in chemical biology, with a particular focus on generating stabilized peptide therapeutics. |
