Aggregation represents a significant challenge for the long-term formulation stability of insulin therapeutics.The supramolecular PEGylation of insulin with conjugates of cucurbit[7]uril and polyethylene glycol(CB[7]-...Aggregation represents a significant challenge for the long-term formulation stability of insulin therapeutics.The supramolecular PEGylation of insulin with conjugates of cucurbit[7]uril and polyethylene glycol(CB[7]-PEG)has been shown to stabilize insulin formulations by reducing aggregation propensity.Yet prolonged in vivo duration of action,arising from sustained complex formation in the subcutaneous depot,limits the application scope for meal-time insulin uses and could increase hypoglycemic risk several hours after a meal.Supramolecular affinity of CB[7]in binding the B1-Phe residue on insulin is central to supramolecular PEGylation using this approach.Accordingly,here we synthesized N-terminal acid-modified insulin analogs to reduce CB[7]interaction affinity at physiological pH and reduce the duration of action by decreasing the subcutaneous depot effect of the formulation.These insulin analogs show weak to no interaction with CB[7]-PEG at physiological pH but demonstrate high formulation stability at reduced pH.Accordingly,N-terminal modified analogs have in vitro and in vivo bioactivity comparable to native insulin.Furthermore,in a rat model of diabetes,the acid-modified insulin formulated with CB[7]-PEG offers a reduced duration of action compared to native insulin formulated with CB[7]-PEG.This work extends the application of supramolecular PEGylation of insulin to achieve enhanced stability while reducing the risks arising from a subcutaneous depot effect prolonging in vivo duration of action.展开更多
基金NIDDK(DK120430,DK121336,USA)to Danny Hung-Chieh ChouJDRF(5-CDA-2020-947-A-N,USA)to Matthew J.Webber。
文摘Aggregation represents a significant challenge for the long-term formulation stability of insulin therapeutics.The supramolecular PEGylation of insulin with conjugates of cucurbit[7]uril and polyethylene glycol(CB[7]-PEG)has been shown to stabilize insulin formulations by reducing aggregation propensity.Yet prolonged in vivo duration of action,arising from sustained complex formation in the subcutaneous depot,limits the application scope for meal-time insulin uses and could increase hypoglycemic risk several hours after a meal.Supramolecular affinity of CB[7]in binding the B1-Phe residue on insulin is central to supramolecular PEGylation using this approach.Accordingly,here we synthesized N-terminal acid-modified insulin analogs to reduce CB[7]interaction affinity at physiological pH and reduce the duration of action by decreasing the subcutaneous depot effect of the formulation.These insulin analogs show weak to no interaction with CB[7]-PEG at physiological pH but demonstrate high formulation stability at reduced pH.Accordingly,N-terminal modified analogs have in vitro and in vivo bioactivity comparable to native insulin.Furthermore,in a rat model of diabetes,the acid-modified insulin formulated with CB[7]-PEG offers a reduced duration of action compared to native insulin formulated with CB[7]-PEG.This work extends the application of supramolecular PEGylation of insulin to achieve enhanced stability while reducing the risks arising from a subcutaneous depot effect prolonging in vivo duration of action.
