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>Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against Mpro and cathepsin L
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Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against Mpro and cathepsin L
The main protease (Msuppro/sup) of SARS-CoV-2 is a key antiviral drug target. While most Msuppro/sup inhibitors have a γ-lactam glutamine surrogate at the P1 position, we recently found that several Msuppro/sup inhibitors have hydrophobic moieties at the P1 site, including calpain inhibitors II and XII, which are also active against human cathepsin L, a host protease that is important for viral entry. In this study, we solved x-ray crystal structures of Msuppro/sup in complex with calpain inhibitors II and XII and three analogs of GC-376 . The structure of Msuppro/sup with calpain inhibitor II confirmed that the S1 pocket can accommodate a hydrophobic methionine side chain, challenging the idea that a hydrophilic residue is necessary at this position. The structure of calpain inhibitor XII revealed an unexpected, inverted binding pose. Together, the biochemical, computational, structural, and cellular data presented herein provide new directions for the development of dual inhibitors as SARS-CoV-2 antivirals.
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机译:SARS-COV-2的主要蛋白酶(m pro sup>)是抗病毒药物靶标。虽然大多数m pro sup>抑制剂在p1位置具有γ-内酰胺谷氨酰胺蛋白酶,但我们最近发现几种m pro sup>抑制剂在p1位点具有疏水性部分,包括CALPAIN抑制剂II和XII也活跃于人体组织蛋白酶L,宿主蛋白酶对病毒进入很重要。在该研究中,我们用Calpain抑制剂II和XII和三种GC-376的三种类似物溶解了M PRO-SUP>的X射线晶体结构。 M PRO SUP>具有CALPAIN抑制剂II的结构证实,S1袋可以容纳疏水性蛋氨酸侧链,具备在该位置需要亲水残留物的想法。 Calpain抑制剂XII的结构揭示了意外,倒置的结合姿势。这里呈现的生物化学,计算,结构和蜂窝数据提供了作为SARS-COV-2抗病毒的双重抑制剂的发展的新方向。
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