Discovery of SARS-CoV-2 3CL(Pro) Peptidomimetic Inhibitors through the Catalytic Dyad Histidine-Specific Protein-Ligand Interactions.
Discovery of SARS-CoV-2 3CL(Pro) Peptidomimetic Inhibitors through the Catalytic Dyad Histidine-Specific Protein-Ligand Interactions.
复制标题
通过催化二元组氨酸特异性蛋白质 - 配体相互作用发现SARS-COV-2 3Cl（Pro）肽型抑制剂。
DOI：
10.3390/ijms23042392
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发表时间：
2022-02-21
影响因子：
5.6
通讯作者：
Ye S
中科院分区：
文献类型：
--
作者：
Wang Y;Xu B;Ma S;Wang H;Shang L;Zhu C;Ye S
作为2019冠状病毒病的病原体，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）对当前的疫苗研发和药物设计工作构成了挑战。由于突破性感染病例不断增多，人们迫切需要广谱抗病毒药物。在此，我们设计并检测了五种新的靶向3C样蛋白酶（3CLPro）的四肽模拟物抗SARS-CoV-2抑制剂，3CLPro在冠状病毒中高度保守，对病毒复制至关重要。基于高分辨率共晶结构、全原子模拟和结合能计算，我们显著提高了一种酮酰胺先导化合物的效力。这些抑制剂如设计预期那样，成功与3CLPro的催化二联体组氨酸残基（H41）结合，在细胞实验中展现出纳摩尔级的抑制能力，并降低了SARS-CoV-2的病毒载量。作为一种广泛适用的设计原则，我们的研究结果表明，3CLPro特异性候选药物的效力取决于3CLPro的H41残基与肽模拟物抑制剂之间的相互作用。
As the etiological agent for the coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenges the ongoing efforts of vaccine development and drug design. Due to the accumulating cases of breakthrough infections, there are urgent needs for broad-spectrum antiviral medicines. Here, we designed and examined five new tetrapeptidomimetic anti-SARS-CoV-2 inhibitors targeting the 3C-Like protease (3CLPro), which is highly conserved among coronaviruses and essential for viral replications. We significantly improved the efficacy of a ketoamide lead compound based on high-resolution co-crystal structures, all-atom simulations, and binding energy calculations. The inhibitors successfully engaged the catalytic dyad histidine residue (H41) of 3CLPro as designed, and they exhibited nanomolar inhibitory capacity as well as mitigated the viral loads of SARS-CoV-2 in cellular assays. As a widely applicable design principle, our results revealed that the potencies of 3CLPro-specific drug candidates were determined by the interplay between 3CLPro H41 residue and the peptidomimetic inhibitors.
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影响因子：
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作者：
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通讯作者：
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64.8
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
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影响因子：
16.6
作者：
Osipiuk J;Azizi SA;Dvorkin S;Endres M;Jedrzejczak R;Jones KA;Kang S;Kathayat RS;Kim Y;Lisnyak VG;Maki SL;Nicolaescu V;Taylor CA;Tesar C;Zhang YA;Zhou Z;Randall G;Michalska K;Snyder SA;Dickinson BC;Joachimiak A
通讯作者：
Joachimiak A
DOI：
10.1126/science.abg5827
发表时间：
2021-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Drayman N;DeMarco JK;Jones KA;Azizi SA;Froggatt HM;Tan K;Maltseva NI;Chen S;Nicolaescu V;Dvorkin S;Furlong K;Kathayat RS;Firpo MR;Mastrodomenico V;Bruce EA;Schmidt MM;Jedrzejczak R;Muñoz-Alía MÁ;Schuster B;Nair V;Han KY;O'Brien A;Tomatsidou A;Meyer B;Vignuzzi M;Missiakas D;Botten JW;Brooke CB;Lee H;Baker SC;Mounce BC;Heaton NS;Severson WE;Palmer KE;Dickinson BC;Joachimiak A;Randall G;Tay S
通讯作者：
Tay S