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首页> 外文期刊>Journal of Molecular Biology >N-Terminal Finger Stabilizes the S1 Pocket for the Reversible Feline Drug GC376 in the SARS-CoV-2 M-pro Dimer
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N-Terminal Finger Stabilizes the S1 Pocket for the Reversible Feline Drug GC376 in the SARS-CoV-2 M-pro Dimer

机译：N末端手指在SARS-COV-2 M-Pro二聚体中稳定可逆猫的S1口袋GC376

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摘要

The main protease (M-pro, also known as 3CL protease) of SARS-CoV-2 is a high priority drug target in the development of antivirals to combat COVID-19 infections. A feline coronavirus antiviral drug, GC376, has been shown to be effective in inhibiting the SARS-CoV-2 main protease and live virus growth. As this drug moves into clinical trials, further characterization of GC376 with the main protease of coronaviruses is required to gain insight into the drug's properties, such as reversibility and broad specificity. Reversibility is an important factor for therapeutic proteolytic inhibitors to prevent toxicity due to off-target effects. Here we demonstrate that GC376 has nanomolar K-i values with the M-pro from both SARS-CoV-2 and SARS-CoV strains. Restoring enzymatic activity after inhibition by GC376 demonstrates reversible binding with both proteases. In addition, the stability and thermodynamic parameters of both proteases were studied to shed light on physical chemical properties of these viral enzymes, revealing higher stability for SARS-CoV-2 M-pro. The comparison of a new X-ray crystal structure of M-pro from SARS-CoV complexed with GC376 reveals similar molecular mechanism of inhibition compared to SARS-CoV-2 M-pro, and gives insight into the broad specificity properties of this drug. In both structures, we observe domain swapping of the N-termini in the dimer of the M-pro, which facilitates coordination of the drug's P1 position. These results validate that GC376 is a drug with an off-rate suitable for clinical trials. (C) 2021 Elsevier Ltd. All rights reserved.
机译：2019冠状病毒疾病的主要蛋白酶（M- PRO，也称3CL蛋白酶）是抗CVID-19感染的抗病毒药物的开发中的一个高优先级的药物靶标。猫冠状病毒抗病毒药物GC376已被证明能有效抑制SARS-CoV-2主要蛋白酶和活病毒的生长。随着该药物进入临床试验，需要进一步鉴定带有冠状病毒主要蛋白酶的GC376，以了解该药物的特性，如可逆性和广泛特异性。可逆性是治疗性蛋白水解抑制剂防止靶向效应毒性的重要因素。在这里，我们证明GC376与来自SARS-CoV-2和SARS-CoV菌株的M-pro具有纳摩尔K-i值。GC376抑制后恢复酶活性表明与这两种蛋白酶的结合是可逆的。此外，研究了这两种蛋白酶的稳定性和热力学参数，以阐明这些病毒酶的物理化学性质，揭示SARS-CoV-2 M-pro具有更高的稳定性。通过比较SARS-CoV-M-pro与GC376复合物的新X射线晶体结构，揭示了与SARS-CoV-2 M-pro相似的抑制分子机制，并深入了解了该药物的广泛特异性。在这两种结构中，我们观察到M-pro二聚体中N-末端的结构域交换，这有助于药物P1位置的协调。这些结果验证了GC376是一种关闭率适合临床试验的药物。（c）2021爱思唯尔有限公司保留所有权利。

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