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Free keywords:
TYPE-2 DIABETES-MELLITUS; CYSTINE-RICH PEPTIDES; DEGRADING ENZYME;
ALZHEIMERS-DISEASE; KINETIC TRAP; SELENOCYSTINE; REPLACEMENT;
DEGRADATION; INHIBITION; MANAGEMENTChemistry; amino acids; drug discovery; protein folding; selenium; structure
elucidation;
Abstract:
Synthetic insulin analogues with a long lifetime are current drug targets for the therapy of diabetic patients. The replacement of the interchain disulfide with a diselenide bridge, which is more resistant to reduction and internal bond rotation, can enhance the lifetime of insulin in the presence of the insulin-degrading enzyme (IDE) without impairing the hormonal function. The [C7U(A), C7U(B)] variant of bovine pancreatic insulin (BPIns) was successfully prepared by using two selenocysteine peptides (i.e., the C7U analogues of A-and B-chains, respectively). In a buffer solution at pH 10 they spontaneously assembled under thermodynamic control to the correct insulin fold. The selenoinsulin (Se-Ins) exhibited a bioactivity comparable to that of BPIns. Interestingly, degradation of Se-Ins with IDE was significantly decelerated (t(1/2) approximate to 8 h vs. approximate to 1 h for BPIns). The lifetime enhancement could be due to both the intrinsic stability of the diselenide bond and local conformational changes induced by the substitution.
