An Aldehyde Responsive, Cleavable Linker for Glucose Responsive Insulins

Research output: Contribution to journalJournal articleResearchpeer-review

  • Karin Mannerstedt
  • Narendra Kumar Mishra
  • Ebbe Engholm
  • Morten Lundh
  • Charlotte S. Madsen
  • Philip J. Pedersen
  • Priska Le‐huu
  • Søren L. Pedersen
  • Nina Buch‐månson
  • Björn Borgström
  • Thomas Brimert
  • Lisbeth N. Fink
  • Keld Fosgerau
  • Niels Vrang
  • Jensen, Knud Jørgen
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.
Original languageEnglish
JournalChemistry: A European Journal
Issue number9
Pages (from-to)3166-3176
Number of pages11
Publication statusPublished - 2021

ID: 258779634