Synthesis of an Arganoinsulin Molecule That Can Be Activated by Antibody Catalysis
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...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2001-11, Vol.98 (24), p.13514-13518 |
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Sprache: | eng |
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Zusammenfassung: | 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 insulinDfor the insulin receptor was reduced by 90% in binding studies using intact cells. The ability of insulinDto stimulate glucose transport was reduced by 96% in 3T3-L1 adipocytes and by 55% in conscious rats. Incubation of insulinDwith the catalytic aldolase antibody 38C2 cleaved all of the aldol-terminated modifications, restoring native insulin. Treatment of insulinDwith 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 insulinDand catalytic antibody 38C2 with potential therapeutic application. |
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ISSN: | 0027-8424 |