García-Aparicio Carlos, Diez-Torrubia Alberto, Balzarini Jan, Lambeir Anne-Marie, Velázquez Sonsoles, Camarasa María-José
Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, E-28006 Madrid, Spain.
Antiviral Res. 2007 Nov;76(2):130-9. doi: 10.1016/j.antiviral.2007.06.009. Epub 2007 Aug 1.
A novel prodrug approach has been evaluated using the anti-HIV-active TSAO molecule as the prototype drug to prove the kinetics with purified enzyme and the principles of conversion to the parent compound in sera and cell culture. When a variety of tetrapeptidyl amide prodrugs of NAP-TSAO were synthesized and exposed to purified dipeptidyl-peptidase IV (DPPIV/CD26) as well as human and bovine sera, they are converted to the parent NAP-TSAO drug in two successive steps by both purified CD26 and human and bovine serum. The efficiency of conversion strongly depends on the nature of the amino acid that has to be cleaved-off from the prodrug molecule. The tetrapeptidyl prodrug 20 showed a more than 10-fold improved water-solubility in comparison to that of the parent compound NAP-TSAO. The antiviral activity of the prototype NAP-TSAO could also be modulated by introducing different tetrapeptide moieties on the molecule resulting, in some cases, in a superior antiviral potential in cell culture than the parent drug.
一种新型前药方法已通过使用抗HIV活性TSAO分子作为原型药物进行评估，以证明其与纯化酶的动力学以及在血清和细胞培养中转化为母体化合物的原理。当合成多种NAP-TSAO的四肽基酰胺前药并将其暴露于纯化的二肽基肽酶IV（DPPIV/CD26）以及人血清和牛血清中时，它们会通过纯化的CD26以及人血清和牛血清分两个连续步骤转化为母体NAP-TSAO药物。转化效率在很大程度上取决于必须从前药分子上切割下来的氨基酸的性质。与母体化合物NAP-TSAO相比，四肽基前药20的水溶性提高了10倍以上。通过在分子上引入不同的四肽部分，也可以调节原型NAP-TSAO的抗病毒活性，在某些情况下，其在细胞培养中的抗病毒潜力优于母体药物。
