Crystal structure of SARS-CoV-2 nsp10-nsp16 in complex with small molecule inhibitors, SS148 and WZ16.
Crystal structure of SARS-CoV-2 nsp10-nsp16 in complex with small molecule inhibitors, SS148 and WZ16.
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DOI：
10.1002/pro.4395
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发表时间：
2022-09
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SARS - CoV - 2 nsp10-nsp16复合体是一种参与病毒RNA盖帽的2 ' - O -甲基转移酶（MTase），使病毒能够逃避人类免疫系统。由于RNA帽的形成对病毒的传播至关重要，它被认为是发现抗病毒疗法的一个有价值的靶标。通过交叉筛选我们之前报道的抑制SARS - CoV - 2 nsp14 MTase活性的抑制剂，我们发现了两种化合物（SS148和WZ16）也能抑制nsp16 MTase活性。为了进一步对这两种化合物进行化学优化，使其成为更有效、更有选择性的双重nsp14/nsp16 MTase抑制剂，我们测定了nsp10-nsp16与SS148和WZ16配合物的晶体结构。正如预期的那样，这些结构揭示了这两种化合物与nsp16的S -腺苷基- L -蛋氨酸（SAM）结合袋的结合。然而，我们的结构数据以及作用机制的生化测定显示，WZ16的抑制是RNA依赖的SAM竞争模式，这清楚地表明，首先结合RNA可能有助于一些SAM竞争抑制剂的结合。这两种化合物对人类蛋白mtase也显示出一定程度的选择性，这表明化学优化具有更强效和选择性的冠状病毒mtase抑制剂的巨大潜力。PDB代码：7R1T和7R1U
SARS‐CoV‐2 nsp10–nsp16 complex is a 2′‐O‐methyltransferase (MTase) involved in viral RNA capping, enabling the virus to evade the immune system in humans. It has been considered a valuable target in the discovery of antiviral therapeutics, as the RNA cap formation is crucial for viral propagation. Through cross‐screening of the inhibitors that we previously reported for SARS‐CoV‐2 nsp14 MTase activity against nsp10–nsp16 complex, we identified two compounds (SS148 and WZ16) that also inhibited nsp16 MTase activity. To further enable the chemical optimization of these two compounds towards more potent and selective dual nsp14/nsp16 MTase inhibitors, we determined the crystal structure of nsp10–nsp16 in complex with each of SS148 and WZ16. As expected, the structures revealed the binding of both compounds to S‐adenosyl‐L‐methionine (SAM) binding pocket of nsp16. However, our structural data along with the biochemical mechanism of action determination revealed an RNA‐dependent SAM‐competitive pattern of inhibition for WZ16, clearly suggesting that binding of the RNA first may help the binding of some SAM competitive inhibitors. Both compounds also showed some degree of selectivity against human protein MTases, an indication of great potential for chemical optimization towards more potent and selective inhibitors of coronavirus MTases. PDB Code(s): 7R1T and 7R1U
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