Genuine selective caspase-2 inhibition with new irreversible small peptidomimetics.
Genuine selective caspase-2 inhibition with new irreversible small peptidomimetics.
复制标题
DOI：
10.1038/s41419-022-05396-2
复制
发表时间：
2022-11-15
影响因子：
9
通讯作者：
Jacotot, Etienne D.
中科院分区：
文献类型：
--
作者：
Bosc, Elodie;Anastasie, Julie;Soualmia, Feryel;Coric, Pascale;Kim, Ju Youn;Wang, Lily Q.;Lacin, Gullen;Zhao, Kaitao;Patel, Ronak;Duplus, Eric;Tixador, Philippe;Sproul, Andrew A.;Brugg, Bernard;Reboud-Ravaux, Michelle;Troy, Carol M.;Shelanski, Michael L.;Bouaziz, Serge;Karin, Michael;El Amri, Chahrazade;Jacotot, Etienne D.
半胱天冬酶-2（Casp 2）是几种人类疾病（包括非酒精性脂肪性肝炎（NASH）和阿尔茨海默病（AD））的有希望的治疗靶点。然而，设计对单个半胱氨酸蛋白酶家族成员具有选择性的活性位点定向抑制剂具有挑战性，因为半胱氨酸蛋白酶具有极其相似的活性位点。在这里，我们提出了新的肽模拟物来自VDVAD五肽结构，窝藏在P2位置的非天然修饰和不可逆的弹头。酶动力学表明，这些新化合物，如LJ 2或其特定异构体LJ 2a和LJ 3a，强烈且不可逆地抑制Casp 2，具有真正的选择性。与Casp 2在细胞应激反应中的既定作用一致，LJ 2抑制由微管不稳定或基于异羟肟酸的脱乙酰酶抑制诱导的细胞死亡。最有效的肽模拟物LJ 2a以非常高的失活率（k3/Ki ~ 5，500，000 M−1 s−1）抑制人Casp 2，而最具选择性的抑制剂LJ 3a对Casp 2的失活率比Casp 3高近1000倍。LJ 3a的结构分析表明，Cα在P2位置的空间构型决定了抑制剂的功效。在过表达位点1蛋白酶（S1 P）、固醇调节元件结合蛋白2（SREBP 2）和Casp 2的转染人细胞系中，LJ 2a和LJ 3a完全抑制Casp 2介导的S1 P切割，从而抑制SREBP 2活化，表明有可能预防NASH发展。此外，在用β-淀粉样蛋白寡聚体处理的原代海马神经元中，亚微摩尔浓度的LJ 2a和LJ 3a防止突触丢失，表明在AD治疗中进一步研究的潜力。
Caspase-2 (Casp2) is a promising therapeutic target in several human diseases, including nonalcoholic steatohepatitis (NASH) and Alzheimer’s disease (AD). However, the design of an active-site-directed inhibitor selective to individual caspase family members is challenging because caspases have extremely similar active sites. Here we present new peptidomimetics derived from the VDVAD pentapeptide structure, harboring non-natural modifications at the P2 position and an irreversible warhead. Enzyme kinetics show that these new compounds, such as LJ2 or its specific isomers LJ2a, and LJ3a, strongly and irreversibly inhibit Casp2 with genuine selectivity. In agreement with the established role of Casp2 in cellular stress responses, LJ2 inhibits cell death induced by microtubule destabilization or hydroxamic acid-based deacetylase inhibition. The most potent peptidomimetic, LJ2a, inhibits human Casp2 with a remarkably high inactivation rate (k3/Ki ~5,500,000 M−1 s−1), and the most selective inhibitor, LJ3a, has close to a 1000 times higher inactivation rate on Casp2 as compared to Casp3. Structural analysis of LJ3a shows that the spatial configuration of Cα at the P2 position determines inhibitor efficacy. In transfected human cell lines overexpressing site-1 protease (S1P), sterol regulatory element-binding protein 2 (SREBP2) and Casp2, LJ2a and LJ3a fully inhibit Casp2-mediated S1P cleavage and thus SREBP2 activation, suggesting a potential to prevent NASH development. Furthermore, in primary hippocampal neurons treated with β-amyloid oligomers, submicromolar concentrations of LJ2a and of LJ3a prevent synapse loss, indicating a potential for further investigations in AD treatment.
登录
查看更多内容
影响因子：
9
作者：
Dhani S;Zhao Y;Zhivotovsky B
通讯作者：
Zhivotovsky B
影响因子：
9
作者：
Machado MV;Michelotti GA;Jewell ML;Pereira TA;Xie G;Premont RT;Diehl AM
通讯作者：
Diehl AM
影响因子：
7.3
作者：
Linton, SD;Aja, T;Zhang, CZ
通讯作者：
Zhang, CZ
影响因子：
3.7
作者：
Deleglise B;Lassus B;Soubeyre V;Alleaume-Butaux A;Hjorth JJ;Vignes M;Schneider B;Brugg B;Viovy JL;Peyrin JM
通讯作者：
Peyrin JM
DOI：
10.1002/trc2.12179
发表时间：
2021
期刊：
Alzheimer's & dementia (New York, N. Y.)
影响因子：
--
作者：
Cummings J;Lee G;Zhong K;Fonseca J;Taghva K
通讯作者：
Taghva K