An Aldehyde Responsive, Cleavable Linker for Glucose Responsive Insulins
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An Aldehyde Responsive, Cleavable Linker for Glucose Responsive Insulins. / Mannerstedt, Karin; Mishra, Narendra Kumar; Engholm, Ebbe; Lundh, Morten; Madsen, Charlotte S.; Pedersen, Philip J.; Le‐huu, Priska; Pedersen, Søren L.; Buch‐månson, Nina; Borgström, Björn; Brimert, Thomas; Fink, Lisbeth N.; Fosgerau, Keld; Vrang, Niels; Jensen, Knud J.
In: Chemistry: A European Journal, Vol. 27, No. 9, 2021, p. 3166-3176.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - An Aldehyde Responsive, Cleavable Linker for Glucose Responsive Insulins
AU - Mannerstedt, Karin
AU - Mishra, Narendra Kumar
AU - Engholm, Ebbe
AU - Lundh, Morten
AU - Madsen, Charlotte S.
AU - Pedersen, Philip J.
AU - Le‐huu, Priska
AU - Pedersen, Søren L.
AU - Buch‐månson, Nina
AU - Borgström, Björn
AU - Brimert, Thomas
AU - Fink, Lisbeth N.
AU - Fosgerau, Keld
AU - Vrang, Niels
AU - Jensen, Knud J.
PY - 2021
Y1 - 2021
N2 - A glucose responsive insulin (GRI) that responds to changes in blood glucose concentrations has remained an elusive goal. Here we describe the development of glucose cleavable linkers based on hydrazone and thiazolidine structures. We developed linkers with low levels of spontaneous hydrolysis but increased level of hydrolysis with rising concentrations of glucose, which demonstrated their glucose responsiveness in vitro. Lipidated hydrazones and thiazolidines were conjugated to the LysB29 side-chain of HI by pH-controlled acylations providing GRIs with glucose responsiveness confirmed in vitro for thiazolidines. Clamp studies showed increased glucose infusion at hyperglycemic conditions for one GRI indicative of a true glucose response. The glucose responsive cleavable linker in these GRIs allow changes in glucose levels to drive the release of active insulin from a circulating depot. We have demonstrated an unprecedented, chemically responsive linker concept for biopharmaceuticals.
AB - A glucose responsive insulin (GRI) that responds to changes in blood glucose concentrations has remained an elusive goal. Here we describe the development of glucose cleavable linkers based on hydrazone and thiazolidine structures. We developed linkers with low levels of spontaneous hydrolysis but increased level of hydrolysis with rising concentrations of glucose, which demonstrated their glucose responsiveness in vitro. Lipidated hydrazones and thiazolidines were conjugated to the LysB29 side-chain of HI by pH-controlled acylations providing GRIs with glucose responsiveness confirmed in vitro for thiazolidines. Clamp studies showed increased glucose infusion at hyperglycemic conditions for one GRI indicative of a true glucose response. The glucose responsive cleavable linker in these GRIs allow changes in glucose levels to drive the release of active insulin from a circulating depot. We have demonstrated an unprecedented, chemically responsive linker concept for biopharmaceuticals.
U2 - 10.1002/chem.202004878
DO - 10.1002/chem.202004878
M3 - Journal article
C2 - 33169429
VL - 27
SP - 3166
EP - 3176
JO - Chemistry: A European Journal
JF - Chemistry: A European Journal
SN - 0947-6539
IS - 9
ER -
ID: 258779634