Silva Daniel G, Ribeiro Jean F R, De Vita Daniela, Cianni Lorenzo, Franco Caio Haddad, Freitas-Junior Lucio H, Moraes Carolina Borsoi, Rocha Josmar R, Burtoloso Antonio C B, Kenny Peter W, Leitão Andrei, Montanari Carlos A
Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil.
Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas, São Paulo, Brazil.
Bioorg Med Chem Lett. 2017 Nov 15;27(22):5031-5035. doi: 10.1016/j.bmcl.2017.10.002. Epub 2017 Oct 3.
The effects on potency of cruzain inhibition of replacing a nitrile group with alternative warheads were explored. The oxime was almost an order of magnitude more potent than the corresponding nitrile and has the potential to provide access to the prime side of the catalytic site. Dipeptide aldehydes and azadipeptide nitriles were found to be two orders of magnitude more potent cruzain inhibitors than the corresponding dipeptide nitriles although potency differences were modulated by substitution at P1 and P3. Replacement of the α methylene of a dipeptide aldehyde with cyclopropane led to a loss of potency of almost three orders of magnitude. The vinyl esters and amides that were characterized as reversible inhibitors were less potent than the corresponding nitrile by between one and two orders of magnitude.
研究了用替代弹头取代腈基对克鲁兹蛋白酶抑制效力的影响。肟的效力比相应的腈高近一个数量级，并且有可能进入催化位点的主要一侧。发现二肽醛和氮杂二肽腈是比相应的二肽腈效力高两个数量级的克鲁兹蛋白酶抑制剂，尽管效力差异受P1和P3处取代的调节。用环丙烷取代二肽醛的α亚甲基导致效力损失近三个数量级。被表征为可逆抑制剂的乙烯基酯和酰胺的效力比相应的腈低一到两个数量级。
