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

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10 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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10.1016/j.celrep.2020.107768

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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

@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.). 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",

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TY - JOUR

T1 - Corrination of a GLP-1 Receptor Agonist for Glycemic Control without Emesis

AU - Borner, Tito

AU - Workinger, Jayme L.

AU - Tinsley, Ian C.

AU - Fortin, Samantha M.

AU - Stein, Lauren M.

AU - Chepurny, Oleg G.

AU - Holz, George G.

AU - Wierzba, Aleksandra J.

AU - Gryko, Dorota

AU - Nexø, Ebba

AU - Shaulson, Evan D.

AU - Bamezai, Ankur

AU - Da Silva, Valentina A.Rodriguez

AU - De Jonghe, Bart C.

AU - Hayes, Matthew R.

AU - Doyle, Robert P.

N1 - 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.). Publisher Copyright: © 2020 The Author(s)

PY - 2020/6/16

Y1 - 2020/6/16

N2 - 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.

AB - 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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KW - anorexia

KW - brain permeability

KW - cobinamide

KW - diabetes

KW - emesis

KW - hypophagia

KW - musk shrew

KW - reduced side effects

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JO - Cell Reports

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

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