@article{211bfa6696c3477486295f81fa280532,
title = "Corrination of a GLP-1 Receptor Agonist for Glycemic Control without Emesis",
abstract = "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.",
keywords = "B12, GLP-1 agonist, anorexia, brain permeability, cobinamide, diabetes, emesis, hypophagia, musk shrew, reduced side effects",
author = "Tito Borner and Workinger, {Jayme L.} and Tinsley, {Ian C.} and Fortin, {Samantha M.} and Stein, {Lauren M.} and Chepurny, {Oleg G.} and Holz, {George G.} and Wierzba, {Aleksandra J.} and Dorota Gryko and Ebba Nex{\o} and Shaulson, {Evan D.} and Ankur Bamezai and {Da Silva}, {Valentina A.Rodriguez} and {De Jonghe}, {Bart C.} and Hayes, {Matthew R.} and Doyle, {Robert P.}",
note = "Funding Information: The authors gratefully acknowledge Prof. Charles C. Horn (University of Pittsburgh) for his assistance and for the supply of the shrews. This work was supported by the National Institutes of Health (grants NIH–DK–097675 to R.P.D., DK112812 to B.C.D.J., DK097675 to M.R.H., DK115762 to M.R.H., and DK069575 to G.G.H.); the Foundation for Polish Sciences ( FNP TEAM POIR.04.04.00–00–4232/17–00 to D.G.); the Swiss National Science Foundation (grants SNF P2ZHP3–178114 and SNF P400PB–186728 to T.B.); and by Xeragenx , St. Louis, Missouri (to R.P.D.). Funding Information: The authors gratefully acknowledge Prof. Charles C. Horn (University of Pittsburgh) for his assistance and for the supply of the shrews. This work was supported by the National Institutes of Health (grants NIH?DK?097675 to R.P.D. DK112812 to B.C.D.J. DK097675 to M.R.H. DK115762 to M.R.H. and DK069575 to G.G.H.); the Foundation for Polish Sciences (FNP TEAM POIR.04.04.00?00?4232/17?00 to D.G.); the Swiss National Science Foundation (grants SNF P2ZHP3?178114 and SNF P400PB?186728 to T.B.); and by Xeragenx, St. Louis, Missouri (to R.P.D.). R.P.D. invented the Cbi-Ex4 technology; T.B. J.L.W. B.C.D.J. M.R.H. and R.P.D. developed the study rationale and experimental designs; T.B. R.P.D. and M.R.H. drafted the manuscript, which was commented on and edited by all authors; T.B. designed and performed most of the in vivo experiments with T.B. B.C.D.J. and M.R.H. analyzing the in vivo data; J.L.W. I.C.T. and R.P.D. generated the constructs and analyzed the structural data; J.L.W. O.G.C. and I.C.T. performed the in vitro experiments with J.L.W. I.C.T. G.G.H. and R.P.D. analyzing the in vitro data; E.N. performed the binding studies on TC and HC; S.M.F. L.M.S. A.J.W. D.G. E.N. E.D.S. A.B. and V.A.R.D.S. performed experiments and/or assisted with data analysis; all authors approved the final version of the manuscript. 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. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = jun,
day = "16",
doi = "10.1016/j.celrep.2020.107768",
language = "English (US)",
volume = "31",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}