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

Autor:	Borner T; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA., Workinger JL; Department of Chemistry, Syracuse University, Syracuse, NY, USA., Tinsley IC; Department of Chemistry, Syracuse University, Syracuse, NY, USA., Fortin SM; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Stein LM; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Chepurny OG; Department of Medicine, Upstate Medical University, State University of New York, Syracuse, NY, USA., Holz GG; Department of Medicine, Upstate Medical University, State University of New York, Syracuse, NY, USA., Wierzba AJ; Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland., Gryko D; Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland., Nexø E; Department of Clinical Biochemistry and Clinical Medicine, University of Aarhus, Aarhus, Denmark., Shaulson ED; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA., Bamezai A; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Da Silva VAR; 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., De Jonghe BC; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA., Hayes MR; 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., Doyle RP; Department of Chemistry, Syracuse University, Syracuse, NY, USA; Department of Medicine, Upstate Medical University, State University of New York, Syracuse, NY, USA. Electronic address: rpdoyle@syr.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2020 Jun 16; Vol. 31 (11), pp. 107768.
DOI:	10.1016/j.celrep.2020.107768
Abstrakt:	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. Competing Interests: Declaration of Interests R.P.D. is a scientific advisory board member and received funds from Balchem Corporation, New Hampton, New York, which were not used in support of these studies. R.P.B. is the named author of a patent pursuant to this work that is owned by Syracuse University. M.R.H. and B.C.D.J. receive funding from Zealand Pharma that was not used in support of these studies. B.C.D.J. receives funding from Pfizer that was not used in support of these studies. M.R.H. receives funding from Novo Nordisk, Eli Lilly & Co. and Boehringer Ingelheim that was not used in support of these studies. All authors declare no other competing financial interests or conflicts of interest. (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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