Abstract
Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has become a global health emergency. Although new vaccines have been generated and being implicated, discovery and application of novel preventive and control measures are warranted. We aimed to identify compounds that may possess the potential to either block the entry of virus to host cells or attenuate its replication upon infection. Using host cell surface receptor expression (angiotensin-converting enzyme 2 (ACE2) and Transmembrane protease serine 2 (TMPRSS2)) analysis as an assay, we earlier screened several synthetic and natural compounds and identified candidates that showed ability to down-regulate their expression. Here, we report experimental and computational analyses of two small molecules, Mortaparib and MortaparibPlus that were initially identified as dual novel inhibitors of mortalin and PARP-1, for their activity against SARS-CoV-2. In silico analyses showed that MortaparibPlus, but not Mortaparib, stably binds into the catalytic pocket of TMPRSS2. In vitro analysis of control and treated cells revealed that MortaparibPlus caused down-regulation of ACE2 and TMPRSS2; Mortaparib did not show any effect. Furthermore, computational analysis on SARS-CoV-2 main protease (Mpro) that also predicted the inhibitory activity of MortaparibPlus. However, cell-based antiviral drug screening assay showed 30–60% viral inhibition in cells treated with non-toxic doses of either MortaparibPlus or Mortaparib. The data suggest that these two closely related compounds possess multimodal anti-COVID-19 activities. Whereas MortaparibPlus works through direct interactions/effects on the host cell surface receptors (ACE2 and TMPRSS2) and the virus protein (Mpro), Mortaparib involves independent mechanisms, elucidation of which warrants further studies.
Highlights
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus that belongs to Coronaviradae family
We used glide flexible molecular docking and examined if Mortaparib or MortaparibPlus could interact with transmembrane protease serine 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2) and act as their inhibitors
These docked complexes were taken further for molecular dynamics (MD) simulation of 100 ns to investigate the stability and dynamic behavior of the proteins when bound to MortaparibPlus
Summary
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus that belongs to Coronaviradae family. Coronaviruses are divided into four major genera (α, β, γ, and δ). SARS-CoV-2 is a β-coronavirus [10,11,12]. The outbreak of novel coronavirus disease 2019 (COVID-19) in the Wuhan province of China by the SARS-CoV-2 was declared a global pandemic by the World Health Organization [13]. SARS-CoV-2 is extremely contagious, several folds more than its previous close relatives, SARS-CoV and MERS coronaviruses [14]. As of 10 September 2021, there are >223 million cases reported with >4.6 million deaths worldwide as recorded by WHO
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