Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: structure-activity relationship study.
Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: structure-activity relationship study.
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DOI：
10.1016/j.ejmech.2013.05.005
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发表时间：
2013-07
影响因子：
6.7
通讯作者：
Hayashi Y
中科院分区：
文献类型：
--
作者：
Thanigaimalai P;Konno S;Yamamoto T;Koiwai Y;Taguchi A;Takayama K;Yakushiji F;Akaji K;Kiso Y;Kawasaki Y;Chen SE;Naser-Tavakolian A;Schön A;Freire E;Hayashi Y
本研究描述了低分子量肽类SARS-CoV 3CL蛋白酶抑制剂的设计、合成和评价。该抑制剂是基于强效三肽Z-Val-Leu-Ala（吡咯烷酮-3-基）-2-苯并噻唑（8;Ki = 4.1 nM）设计的，其中P3缬氨酸单元被多种不同的部分取代。所得到的二肽型抑制剂对3CLpro具有中等至良好的抑制活性。其中化合物26m和26n表现出较好的抑制活性，Ki值分别为0.39和0.33 μM。这些低分子量化合物为进一步开发具有药物特性的强效拟肽抑制剂提供了有吸引力的线索。对接研究模拟了化合物26m与SARS-CoV 3CL蛋白酶的结合相互作用。对具有有效抑制活性的拟肽化合物的初步SAR研究揭示了几个增强抑制活性的结构特征：(i) S1 '位置的苯并噻唑战斗部，（ii） S1位置的γ-内酰胺单元，（iii） s2位置的适当疏水亮氨酸片段，以及（iv）在s3位置的n -芳基甘氨酸单元和主氢键供体之间的氢键。
This work describes the design, synthesis, and evaluation of low-molecular weight peptidic SARS-CoV 3CL protease inhibitors. The inhibitors were designed based on the potent tripeptidic Z-Val-Leu-Ala(pyrrolidone-3-yl)-2-benzothiazole (8; Ki = 4.1 nM), in which the P3 valine unit was substituted with a variety of distinct moieties. The resulting series of dipeptide-type inhibitors displayed moderate to good inhibitory activities against 3CLpro. In particular, compounds 26m and 26n exhibited good inhibitory activities with Ki values of 0.39 and 0.33 μM, respectively. These low-molecular weight compounds are attractive leads for the further development of potent peptidomimetic inhibitors with pharmaceutical profiles. Docking studies were performed to model the binding interaction of the compound 26m with the SARS-CoV 3CL protease. The preliminary SAR study of the peptidomimetic compounds with potent inhibitory activities revealed several structural features that boosted the inhibitory activity: (i) a benzothiazole warhead at the S1′ position, (ii) a γ-lactam unit at the S1-position, (iii) an appropriately hydrophobic leucine moiety at the S2-position, and (iv) a hydrogen bond between the N-arylglycine unit and a backbone hydrogen bond donor at the S3-position.
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影响因子：
1.8
作者：
Tian, QP;Nayyar, NK;Kennedy, TP
通讯作者：
Kennedy, TP
影响因子：
3.5
作者：
Konno S;Thanigaimalai P;Yamamoto T;Nakada K;Kakiuchi R;Takayama K;Yamazaki Y;Yakushiji F;Akaji K;Kiso Y;Kawasaki Y;Chen SE;Freire E;Hayashi Y
通讯作者：
Hayashi Y
DOI：
10.1016/s0140-6736(03)13077-2
发表时间：
2003-04-19
期刊：
Lancet (London, England)
影响因子：
--
作者：
Peiris JS;Lai ST;Poon LL;Guan Y;Yam LY;Lim W;Nicholls J;Yee WK;Yan WW;Cheung MT;Cheng VC;Chan KH;Tsang DN;Yung RW;Ng TK;Yuen KY;SARS study group
通讯作者：
SARS study group
影响因子：
2.9
作者：
Barrila, Jennifer;Bacha, Usman;Freire, Ernesto
通讯作者：
Freire, Ernesto
影响因子：
56.9
作者：
Anand, K;Ziebuhr, J;Hilgenfeld, R
通讯作者：
Hilgenfeld, R