Design and synthesis of naturally-inspired SARS-CoV-2 inhibitors.
Design and synthesis of naturally-inspired SARS-CoV-2 inhibitors.
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自然启发的 SARS-CoV-2 抑制剂的设计和合成。
DOI：
10.1039/d2md00149g
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发表时间：
2023
影响因子：
4.1
通讯作者：
Arimondo,PaolaB
中科院分区：
文献类型：
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作者：
Hassan,Haitham;Chiavaralli,Jeanne;Hassan,Afnan;Bedda,Loay;Krischuns,Tim;Chen,Kuang-Yu;Li,AliceShiMing;Delpal,Adrien;Decroly,Etienne;Vedadi,Masoud;Naffakh,Nadia;Agou,Fabrice;Mallart,Sergio;Arafa,ReemK;Arimondo,PaolaB
一个由25个分子组成的自然灵感化学库在三维维度和天然产物相似因子的指导下合成，以探索新的化学空间。合成的化学库由稠合桥连的十二氢-2a，6-环氧氮杂卓并[3，4，5-c，d]吲哚骨架组成，在分子量、C-sp3分数和Clog P方面遵循铅相似因子。 对25种化合物进行抗SARS-CoV-2感染的肺细胞的筛选，鉴定出2种命中物。尽管化学文库显示出细胞毒性，但两个命中物（3b，9 e）显示出最高的抗病毒活性（EC 50值分别为3.7和1.4 μM），具有可接受的细胞毒性差异。对SARS-CoV-2的主要蛋白靶点（主要蛋白酶Mpro、核衣壳磷蛋白、非结构蛋白nsp 10-nsp 16复合物和RBD/ACE 2复合物）进行了基于对接和分子动力学模拟的计算分析。计算分析提出可能的结合靶点是Mpro或nsp 10-nsp 16复合物。进行生物测定以证实这一主张。使用反向纳米荧光素酶（Rev-Nluc）报告基因的Mpro蛋白酶活性的基于细胞的测定证实了3b靶向Mpro。这些结果为进一步优化命中率开辟了道路。
A naturally inspired chemical library of 25 molecules was synthesised guided by 3-D dimensionality and natural product likeness factors to explore a new chemical space. The synthesised chemical library, consisting of fused-bridged dodecahydro-2a,6-epoxyazepino[3,4,5-c,d]indole skeletons, followed lead likeness factors in terms of molecular weight, C-sp3 fraction and Clog P. Screening of the 25 compounds against lung cells infected with SARS-CoV-2 led to the identification of 2 hits. Although the chemical library showed cytotoxicity, the two hits (3b, 9e) showed the highest antiviral activity (EC50 values of 3.7 and 1.4 μM, respectively) with an acceptable cytotoxicity difference. Computational analysis based on docking and molecular dynamics simulations against main protein targets in SARS-CoV-2 (main protease Mpro, nucleocapsid phosphoprotein, non-structural protein nsp10–nsp16 complex and RBD/ACE2 complex) were performed. The computational analysis proposed the possible binding targets to be either Mpro or the nsp10–nsp16 complex. Biological assays were performed to confirm this proposition. A cell-based assay for Mpro protease activity using a reverse-nanoluciferase (Rev-Nluc) reporter confirmed that 3b targets Mpro. These results open the way towards further hit-to-lead optimisations.