Levy O E, Taibi P, Mobashery S, Ghosh S S
Salk Biotechnology/Industrial Associates, Inc., La Jolla, California 92138.
J Med Chem. 1993 Aug 6;36(16):2408-11. doi: 10.1021/jm00068a019.
The mechanism-based inactivation of human neutral endopeptidase 24.11 (NEP) was studied with N-[(R)-2-benzyl-5-cyano-4-oxopentanoyl]-L-phenylalanine (1) and its peptidic analogue, N(-)[N-(cyanoacetyl)-L-phenylalanyl]-L-phenylalanine (2). While both these active-site-directed molecules inactivate NEP, the related angiotensin-converting enzyme (ACE) is only inactivated by compound 2 [Ghosh et al. J. Med. Chem. 1992, 35, 4175-4179]. The selectivity in inactivation was addressed further by a comparative study of the interaction of compounds 1 and 2 with five other zinc proteases. The selective inactivation of NEP observed with the ketomethylene compound 1 suggests that the active site of NEP is less discriminating in its requirements for binding such substrate analogues as compared to ACE, a characteristic that may be exploited for designing specific mechanism-based inactivators for NEP. It is proposed that the inactivation is a result of NEP-catalyzed formation of ketenimine intermediates, which are subsequently trapped by an active-site nucleophile.
利用N-[(R)-2-苄基-5-氰基-4-氧代戊酰基]-L-苯丙氨酸（1）及其肽类似物N-[(氰基乙酰基)-L-苯丙氨酰基]-L-苯丙氨酸（2）研究了基于机制的人中性内肽酶24.11（NEP）失活情况。虽然这两种活性位点导向分子都会使NEP失活，但相关的血管紧张素转换酶（ACE）仅被化合物2失活[戈什等人，《药物化学杂志》，1992年，35卷，4175 - 4179页]。通过比较化合物1和2与其他五种锌蛋白酶的相互作用，进一步探讨了失活的选择性。用酮亚甲基化合物1观察到的NEP选择性失活表明，与ACE相比，NEP的活性位点在结合此类底物类似物的要求上辨别能力较弱，这一特性可用于设计基于机制的NEP特异性失活剂。有人提出，失活是NEP催化形成烯酮亚胺中间体的结果，随后这些中间体被活性位点亲核试剂捕获。
