Hochuli Joshua E, Jain Sankalp, Melo-Filho Cleber, Sessions Zoe L, Bobrowski Tesia, Choe Jun, Zheng Johnny, Eastman Richard, Talley Daniel C, Rai Ganesha, Simeonov Anton, Tropsha Alexander, Muratov Eugene N, Baljinnyam Bolormaa, Zakharov Alexey V
Molecular Modeling Laboratory, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC.
Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC.
bioRxiv. 2022 Mar 16:2022.03.15.484484. doi: 10.1101/2022.03.15.484484.
The COVID-19 pandemic has had enormous health, economic, and social consequences. Vaccines have been successful in reducing rates of infection and hospitalization, but there is still a need for an acute treatment for the disease. We investigate whether compounds that bind the human ACE2 protein can interrupt SARS-CoV-2 replication without damaging ACE2’s natural enzymatic function. Initial compounds were screened for binding to ACE2 but little interruption of ACE2 enzymatic activity. This set of compounds was extended by application of quantitative structure-activity analysis, which resulted in 512 virtual hits for further confirmatory screening. A subsequent SARS-CoV-2 replication assay revealed that five of these compounds inhibit SARS-CoV-2 replication in human cells. Further effort is required to completely determine the antiviral mechanism of these compounds, but they serve as a strong starting point for both development of acute treatments for COVID-19 and research into the mechanism of infection.
新冠疫情已造成了巨大的健康、经济和社会影响。疫苗在降低感染率和住院率方面取得了成功，但仍需要针对该疾病的急性治疗方法。我们研究了与人类ACE2蛋白结合的化合物是否能在不损害ACE2天然酶功能的情况下中断新冠病毒的复制。最初筛选了与ACE2结合的化合物，但对ACE2酶活性的干扰很小。通过应用定量构效分析扩展了这组化合物，这产生了512个虚拟命中物用于进一步的验证性筛选。随后的新冠病毒复制试验表明，这些化合物中有五种可抑制人类细胞中的新冠病毒复制。要完全确定这些化合物的抗病毒机制还需要进一步努力，但它们是开发新冠急性治疗方法和研究感染机制的有力起点。
