期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2001
卷号：98
期号：24
页码：13514-13518
DOI：10.1073/pnas.241516698
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：We have developed a methodology of prodrug delivery by using a modified insulin species whose biological activity potentially can be regulated in vivo. Native insulin was derivatized with aldol-terminated chemical modifications that can be selectively removed by the catalytic aldolase antibody 38C2 under physiologic conditions. The derivatized organoinsulin (insulinD) was defective with respect to receptor binding and stimulation of glucose transport. The affinity of insulinD for the insulin receptor was reduced by 90% in binding studies using intact cells. The ability of insulinD to stimulate glucose transport was reduced by 96% in 3T3-L1 adipocytes and by 55% in conscious rats. Incubation of insulinD with the catalytic aldolase antibody 38C2 cleaved all of the aldol-terminated modifications, restoring native insulin. Treatment of insulinD with 38C2 also restored insulinD's receptor binding and glucose transport-stimulating activities in vitro, as well as its ability to lower glucose levels in animals in vivo. We propose that these results are the foundation for an in vivo regulated system of insulin activation using the prohormone insulinD and catalytic antibody 38C2 with potential therapeutic application.
