Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety.
Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety.
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DOI：
10.1016/j.bmc.2012.11.017
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发表时间：
2013-01-15
影响因子：
3.5
通讯作者：
Hayashi Y
中科院分区：
文献类型：
--
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
我们在这里描述了一系列分子的设计、合成和生物学评价，以开发SARS-CoV 3CLpro的新型拟肽抑制剂。一项涉及初始先导化合物1和SARS-CoV 3CLpro之间结合的对接研究激发了在P1′位点用苯并噻唑单元取代噻唑作为弹头部分。这种修饰导致鉴定出更有效的衍生物，包括2 i、2k、2 m、2 o和2 p，其IC 50或Ki值在亚微摩尔至纳摩尔范围内。特别是，化合物2 i和2 p表现出最有效的抑制活性，Ki值分别为4.1和3.1 nM。通过这一过程确定的拟肽化合物是有吸引力的线索，为开发潜在的治疗药物，以对抗SARS。对SARS-CoV 3CLpro具有有效抑制活性的肽模拟物的结构要求可概括如下：（i）在S1′-位存在苯并噻唑弹头;（ii）在S1-位的环内酰胺上具有氢键结合能力;（iii）在S2-位点处的适当立体化学和疏水部分大小，以及（iv）S4位点的苯氧乙酰基部分呈现独特的折叠构象。
We describe here the design, synthesis and biological evaluation of a series of molecules toward the development of novel peptidomimetic inhibitors of SARS-CoV 3CLpro. A docking study involving binding between the initial lead compound 1 and the SARS-CoV 3CLpro motivated the replacement of a thiazole with a benzothiazole unit as a warhead moiety at the P1′ site. This modification led to the identification of more potent derivatives, including 2i, 2k, 2m, 2o, and 2p, with IC50 or Ki values in the submicromolar to nanomolar range. In particular, compounds 2i and 2p exhibited the most potent inhibitory activities, with Ki values of 4.1 and 3.1 nM, respectively. The peptidomimetic compounds identified through this process are attractive leads for the development of potential therapeutic agents against SARS. The structural requirements of the peptidomimetics with potent inhibitory activities against SARS-CoV 3CLpro may be summarized as follows: (i) the presence of a benzothiazole warhead at the S1′-position; (ii) hydrogen bonding capabilities at the cyclic lactam of the S1-site; (iii) appropriate stereochemistry and hydrophobic moiety size at the S2-site and (iv) a unique folding conformation assumed by the phenoxyacetyl moiety at the S4-site.
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影响因子：
1.8
作者：
Tian, QP;Nayyar, NK;Kennedy, TP
通讯作者：
Kennedy, TP
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
影响因子：
2.1
作者：
Sydnes, Magne O.;Hayashi, Yoshio;Kiso, Yoshiaki
通讯作者：
Kiso, Yoshiaki