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

doi:10.1016/j.celrep.2020.107768

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

Research output: Contribution to journal › Article

1 Scopus citations

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.

Original language	English (US)
Article number	107768
Journal	Cell Reports
Volume	31
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2020.107768
State	Published - Jun 16 2020

Keywords

B12
GLP-1 agonist
anorexia
brain permeability
cobinamide
diabetes
emesis
hypophagia
musk shrew
reduced side effects

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Borner, T., Workinger, J. L., Tinsley, I. C., Fortin, S. M., Stein, L. M., Chepurny, O. G., Holz, G. G., Wierzba, A. J., Gryko, D., Nexø, E., Shaulson, E. D., Bamezai, A., Da Silva, V. A. R., De Jonghe, B. C., Hayes, M. R., & Doyle, R. P. (2020). Corrination of a GLP-1 Receptor Agonist for Glycemic Control without Emesis. Cell Reports, 31(11), [107768]. https://doi.org/10.1016/j.celrep.2020.107768

Corrination of a GLP-1 Receptor Agonist for Glycemic Control without Emesis. / Borner, Tito; Workinger, Jayme L.; Tinsley, Ian C.; Fortin, Samantha M.; Stein, Lauren M.; Chepurny, Oleg G.; Holz, George G.; Wierzba, Aleksandra J.; Gryko, Dorota; Nexø, Ebba; Shaulson, Evan D.; Bamezai, Ankur; Da Silva, Valentina A.Rodriguez; De Jonghe, Bart C.; Hayes, Matthew R.; Doyle, Robert P.

In: Cell Reports, Vol. 31, No. 11, 107768, 16.06.2020.

Research output: Contribution to journal › Article

Borner, Tito ; Workinger, Jayme L. ; Tinsley, Ian C. ; Fortin, Samantha M. ; Stein, Lauren M. ; Chepurny, Oleg G. ; Holz, George G. ; Wierzba, Aleksandra J. ; Gryko, Dorota ; Nexø, Ebba ; Shaulson, Evan D. ; Bamezai, Ankur ; Da Silva, Valentina A.Rodriguez ; De Jonghe, Bart C. ; Hayes, Matthew R. ; Doyle, Robert P. / Corrination of a GLP-1 Receptor Agonist for Glycemic Control without Emesis. In: Cell Reports. 2020 ; Vol. 31, No. 11.

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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.",

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AU - Shaulson, Evan D.

AU - Bamezai, Ankur

AU - Da Silva, Valentina A.Rodriguez

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