Insulin derivatives such as insulin detemir and insulin degludec are U.S.Food and Drug Administration(FDA)-approved long-acting insulin currently used by millions of people with diabetes.These derivatives are modified...Insulin derivatives such as insulin detemir and insulin degludec are U.S.Food and Drug Administration(FDA)-approved long-acting insulin currently used by millions of people with diabetes.These derivatives are modified in C-terminal B29 lysine to retain insulin bioactivity.New and efficient methods for facile synthesis of insulin derivatives may lead to new discovery of therapeutic insulin.Herein,we report a new method using sortase A(SrtA)-mediated ligation for the synthesis of insulin derivatives with high efficiency and functional group tolerance in the C-terminal B chain.This new insulin molecule(Ins-SA) with an SrtA-recognizing motif can be conjugated to diverse groups with N-terminal oligoglycines to generate new insulin derivatives.We further demonstrated that a new insulin derivative synthesized by this SrtA-mediated ligation shows strong cellular and in vivo bioactivity.This enzymatic method can therefore be used for future insulin design and development.展开更多
基金supported by NIGMS(GM125001,USA)NIDDK(DK121336,USA)
文摘Insulin derivatives such as insulin detemir and insulin degludec are U.S.Food and Drug Administration(FDA)-approved long-acting insulin currently used by millions of people with diabetes.These derivatives are modified in C-terminal B29 lysine to retain insulin bioactivity.New and efficient methods for facile synthesis of insulin derivatives may lead to new discovery of therapeutic insulin.Herein,we report a new method using sortase A(SrtA)-mediated ligation for the synthesis of insulin derivatives with high efficiency and functional group tolerance in the C-terminal B chain.This new insulin molecule(Ins-SA) with an SrtA-recognizing motif can be conjugated to diverse groups with N-terminal oligoglycines to generate new insulin derivatives.We further demonstrated that a new insulin derivative synthesized by this SrtA-mediated ligation shows strong cellular and in vivo bioactivity.This enzymatic method can therefore be used for future insulin design and development.
