Characterization of caspase-2 inhibitors based on specific sites of caspase-2-mediated proteolysis.
Characterization of caspase-2 inhibitors based on specific sites of caspase-2-mediated proteolysis.
复制标题
DOI：
10.1002/ardp.202200095
复制
发表时间：
2022-09
影响因子：
5.1
通讯作者：
Pockes, Steffen
中科院分区：
文献类型：
--
作者：
Bresinsky, Merlin;Strasser, Jessica M.;Hubmann, Alexander;Vallaster, Bernadette;McCue, William M.;Fuller, Jessica;Singh, Gurpreet;Nelson, Kathryn M.;Cuellar, Matthew E.;Finzel, Barry C.;Ashe, Karen H.;Walters, Michael A.;Pockes, Steffen
自从发现caspase-2（Casp 2）介导的Δ tau 314切割产物及其对tau蛋白病如阿尔茨海默病的相关影响以来，选择性Casp 2抑制剂的设计已成为药物化学研究的焦点。在寻找与Casp 2选择性和药物相似性有关的新的先导结构时，我们采取了一种方法，即更密切地观察Casp 2介导的蛋白水解的特定位点。使用七个选定的蛋白质切割序列，我们合成了一系列的53个新分子的肽，并研究了他们在体外药理学，分子建模和晶体学。关于Casp 2选择性，AcITV（Dab）D-CHO（23）和AcITV（Dap）D-CHO（26）显示出最好的选择性（1-6倍），尽管这些趋势仅是中等的。然而，一些类似的四肽，最值得注意的是AcDKVD-CHO（45），显示出显著增加的Casp 3选择性（>100倍）。四肽和三肽显示出降低的Casp 2活性或没有Casp 2活性，这支持了有效的Casp 2抑制需要五个氨基酸的基序的假设。总的来说，这些结果为选择性caspase-2和caspase-3抑制剂的开发提供了合理的基础。在寻找新的先导化合物的胱天蛋白酶-2（Casp 2）抑制和药物适用性方面，我们检查了特定的网站Casp 2介导的蛋白水解。选择的蛋白质切割序列产生推导的抑制剂，例如AcGESD-CHO、AcLDVPD-CHO、AcFDVPD-CHO和AcITVKD-CHO，其形成我们的53种肽系列的基础。在晶体学（Casp 3）和分子建模的数据支持下，出现了进一步开发选择性caspase-2抑制剂的重要见解。
Since the discovery of the caspase-2 (Casp2)-mediated Δtau314 cleavage product and its associated impact on tauopathies such as Alzheimer's disease, the design of selective Casp2 inhibitors has become a focus in medicinal chemistry research. In the search for new lead structures with respect to Casp2 selectivity and druglikeness, we have taken an approach by looking more closely at the specific sites of Casp2-mediated proteolysis. Using seven selected protein cleavage sequences, we synthesized a peptide series of 53 novel molecules and studied them using in vitro pharmacology, molecular modeling, and crystallography. Regarding Casp2 selectivity, AcITV(Dab)D-CHO (23) and AcITV(Dap)D-CHO (26) demonstrated the best selectivity (1-6-fold), although these trends were only moderate. However, some analogous tetrapeptides, most notably AcDKVD-CHO (45), showed significantly increased Casp3 selectivities (>100-fold). Tetra- and tripeptides display decreased or no Casp2 activity which support the assumption that a motif of five amino acids is required for efficient Casp2 inhibition. Overall, the results provide a reasonable basis for the development of both selective caspase-2 and caspase-3 inhibitors. In search of new lead compounds in terms of caspase-2 (Casp2) inhibition and drug suitability we examined specific sites of Casp2-mediated proteolysis. Selected protein cleavage sequences yielded deduced inhibitors such as AcGESPD-CHO, AcLDVPD-CHO, AcFDVPD-CHO, and AcITVKD-CHO which form the basis for our series of 53 peptides. Supported by data from crystallography (Casp3) and molecular modelin, important insights for the further development of selective caspase-2 inhibitors emerged.
登录
查看更多内容
影响因子：
15.1
作者：
Carroll JB;Southwell AL;Graham RK;Lerch JP;Ehrnhoefer DE;Cao LP;Zhang WN;Deng Y;Bissada N;Henkelman RM;Hayden MR
通讯作者：
Hayden MR
影响因子：
16.2
作者：
Hoover, Brian R.;Reed, Miranda N.;Su, Jianjun;Penrod, Rachel D.;Kotilinek, Linda A.;Grant, Marianne K.;Pitstick, Rose;Carlson, George A.;Lanier, Lorene M.;Yuan, Li-Lian;Ashe, Karen H.;Liao, Dezhi
通讯作者：
Liao, Dezhi
影响因子：
7.2
作者：
Agniswamy, Johnson;Fang, Bin;Weber, Irene T.
通讯作者：
Weber, Irene T.
影响因子：
5.4
作者：
Agniswamy, Johnson;Fang, Bin;Weber, Irene T.
通讯作者：
Weber, Irene T.
影响因子：
7.3
作者：
Choong, IC;Lew, W;O'Brien, T
通讯作者：
O'Brien, T