Corrination of a GLP-1 Receptor Agonist for Glycemic Control without Emesis

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  • Tito Borner, University of Pennsylvania
  • ,
  • Jayme L. Workinger, Syracuse University
  • ,
  • Ian C. Tinsley, Syracuse University
  • ,
  • Samantha M. Fortin, University of Pennsylvania
  • ,
  • Lauren M. Stein, University of Pennsylvania
  • ,
  • Oleg G. Chepurny, State University of New York
  • ,
  • George G. Holz, State University of New York
  • ,
  • Aleksandra J. Wierzba, Polish Academy of Sciences
  • ,
  • Dorota Gryko, Polish Academy of Sciences
  • ,
  • Ebba Nexø
  • Evan D. Shaulson, University of Pennsylvania
  • ,
  • Ankur Bamezai, University of Pennsylvania
  • ,
  • Valentina A.Rodriguez Da Silva, University of Pennsylvania
  • ,
  • Bart C. De Jonghe, University of Pennsylvania
  • ,
  • Matthew R. Hayes, University of Pennsylvania
  • ,
  • Robert P. Doyle, Syracuse University, State University of New York

Glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat type 2 diabetes mellitus often produce nausea, vomiting, and in some patients, undesired anorexia. Notably, these behavioral effects are caused by direct central GLP-1R activation. Herein, we describe the creation of a GLP-1R agonist conjugate with modified brain penetrance that enhances GLP-1R-mediated glycemic control without inducing vomiting. Covalent attachment of the GLP-1R agonist exendin-4 (Ex4) to dicyanocobinamide (Cbi), a corrin ring containing precursor of vitamin B12, produces a “corrinated” Ex4 construct (Cbi-Ex4). Data collected in the musk shrew (Suncus murinus), an emetic mammal, reveal beneficial effects of Cbi-Ex4 relative to Ex4, as evidenced by improvements in glycemic responses in glucose tolerance tests and a profound reduction of emetic events. Our findings highlight the potential for clinical use of Cbi-Ex4 for millions of patients seeking improved glycemic control without common side effects (e.g., emesis) characteristic of current GLP-1 therapeutics.

OriginalsprogEngelsk
Artikelnummer107768
TidsskriftCell Reports
Vol/bind31
Nummer11
ISSN2211-1247
DOI
StatusUdgivet - jun. 2020

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