Corrination of a GLP-1 Receptor Agonist for Glycemic Control without Emesis
Tito Borner,
Jayme L. Workinger,
Ian C. Tinsley,
Samantha M. Fortin,
Lauren M. Stein,
Oleg G. Chepurny,
George G. Holz,
Aleksandra J. Wierzba,
Dorota Gryko,
Ebba Nexø,
Evan D. Shaulson,
Ankur Bamezai,
Valentina A. Rodriguez Da Silva,
Bart C. De Jonghe,
Matthew R. Hayes,
Robert P. Doyle
Affiliations
Tito Borner
Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
Jayme L. Workinger
Department of Chemistry, Syracuse University, Syracuse, NY, USA
Ian C. Tinsley
Department of Chemistry, Syracuse University, Syracuse, NY, USA
Samantha M. Fortin
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Lauren M. Stein
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Oleg G. Chepurny
Department of Medicine, Upstate Medical University, State University of New York, Syracuse, NY, USA
George G. Holz
Department of Medicine, Upstate Medical University, State University of New York, Syracuse, NY, USA
Aleksandra J. Wierzba
Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland
Dorota Gryko
Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland
Ebba Nexø
Department of Clinical Biochemistry and Clinical Medicine, University of Aarhus, Aarhus, Denmark
Evan D. Shaulson
Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
Ankur Bamezai
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Valentina A. Rodriguez Da Silva
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
Bart C. De Jonghe
Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
Matthew R. Hayes
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
Robert P. Doyle
Department of Chemistry, Syracuse University, Syracuse, NY, USA; Department of Medicine, Upstate Medical University, State University of New York, Syracuse, NY, USA; Corresponding author
Summary: 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.
