The cobalt(III)-insulin hexamer is a prolonged-acting insulin prodrug.
The insulin hexamer has two high-affinity metal ion binding sites, each involving three HisB10 residues, one from each dimer. Insulin hexamers containing Co2+ at both these sites were oxidized to form a stable Co(3+)-insulin complex. It is shown that the Co(3+)-coordinated insulin monomers are released extremely slowly in aqueous solution at pH 8.0, and that the hexamer does not spontaneously dissociate into subunits at nanomolar concentrations of insulin. The Co(3+)-insulin hexamer is not recognized by the insulin receptor in vitro but the complex shows a protracted action profile following subcutaneous (s.c.) injection into rabbits. The Co(3+)-insulin hexamer provides a novel prodrug approach to a soluble, prolonged-acting insulin preparation of potential use for basal insulin delivery in the treatment of diabetes.
Kurtzhals
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P
Novo Research Institute, Novo Nordisk A/S, Novo Alle, Bagsvaerd, Denmark.
Kiehr
B
B
Sørensen
A R
AR
D000818:Animals; D001665:Binding Sites; D001786:Blood Glucose / Q000187:drug effects*; D003035:Cobalt / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D008297:Male; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D011972:Receptor, Insulin / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D008024:Ligands; D009942:Organometallic Compounds; D011355:Prodrugs; D003035:Cobalt; D011972:Receptor, Insulin