Novel Inhibitors of Severe Acute Respiratory Syndrome Coronavirus Entry That Act by Three Distinct Mechanisms
Novel Inhibitors of Severe Acute Respiratory Syndrome Coronavirus Entry That Act by Three Distinct Mechanisms
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DOI：
10.1128/jvi.00998-13
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发表时间：
2013-07-01
影响因子：
5.4
通讯作者：
Sarafianos, Stefan G.
中科院分区：
文献类型：
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作者：
Adedeji, Adeyemi O.;Severson, William;Sarafianos, Stefan G.
严重急性呼吸道综合征（SARS）是一种由SARS冠状病毒（SARS-CoV）引起的传染性和高度接触性疾病，目前还没有批准的治疗方法。我们报告了SARS-CoV复制的小分子抑制剂的发现和表征，这些抑制剂通过三种不同的机制阻断病毒进入。这些化合物是通过筛选化合物库发现的，这些化合物用于阻断用SARS-CoV表面糖蛋白S（SARS-S）假型化的HIV-1进入，但不阻断用水泡性口炎病毒表面糖蛋白G（VSV-G）假型化的HIV-1进入。对它们的作用机制的研究表明，化合物通过三种不同的机制起作用：（i）SSAA 09 E2 {N-[[4-（4-氨基苯基）-2-甲基-2-氧代-3-甲基-2-氧代-2-氧代（4-甲基-哌嗪-1-基）苯基]甲基]-1，2-恶唑-5-甲酰胺}通过一种新的作用机制发挥作用，通过阻断SARS-S与SARS-CoV受体血管紧张素转换酶2（ACE 2）的早期相互作用;（ii）SSAA 09 E1 {[（Z）-1-噻吩-2-亚乙基氨基]硫脲}通过阻断组织蛋白酶L（一种在病毒进入期间处理SARS-S所需的宿主蛋白酶）而稍后起作用;及（iii）SSAA 09 E3 [N-（9，10-二氧代-9，10-二氢蒽-2-基）苯甲酰胺]也作用较晚，不影响SARS-S与ACE 2或组织蛋白酶L的酶功能，但阻止病毒膜与宿主细胞膜的融合。我们的工作表明，至少有三个独立的策略来阻止SARS-CoV进入，验证了这些抑制机制，并为SARS治疗药物的开发引入了有前途的线索。
Severe acute respiratory syndrome (SARS) is an infectious and highly contagious disease that is caused by SARS coronavirus (SARS-CoV) and for which there are currently no approved treatments. We report the discovery and characterization of small-molecule inhibitors of SARS-CoV replication that block viral entry by three different mechanisms. The compounds were discovered by screening a chemical library of compounds for blocking of entry of HIV-1 pseudotyped with SARS-CoV surface glycoprotein S (SARS-S) but not that of HIV-1 pseudotyped with vesicular stomatitis virus surface glycoprotein G (VSV-G). Studies on their mechanisms of action revealed that the compounds act by three distinct mechanisms: (i) SSAA09E2 {N-[[4-(4-methyl-piperazin-1-yl)phenyl]methyl]-1,2-oxazole-5-carboxamide} acts through a novel mechanism of action, by blocking early interactions of SARS-S with the receptor for SARS-CoV, angiotensin converting enzyme 2 (ACE2); (ii) SSAA09E1 {[(Z)-1-thiophen-2-ylethylideneamino]thiourea} acts later, by blocking cathepsin L, a host protease required for processing of SARS-S during viral entry; and (iii) SSAA09E3 [N-(9,10-dioxo-9,10-dihydroanthracen-2-yl)benzamide] also acts later and does not affect interactions of SARS-S with ACE2 or the enzymatic functions of cathepsin L but prevents fusion of the viral membrane with the host cellular membrane. Our work demonstrates that there are at least three independent strategies for blocking SARS-CoV entry, validates these mechanisms of inhibition, and introduces promising leads for the development of SARS therapeutics.