Abstract
SARS-CoV-2 Spike protein was predicted by molecular docking to bind the host cell surface GRP78, which was suggested as a putative good molecular target to inhibit Covid-19. We aimed to confirm that GRP78 gene expression was increased in blood of SARS-CoV-2 (+) versus SARS-CoV-2 (−) pneumonia patients. In addition, we aimed to identify drugs that could be repurposed to inhibit GRP78, thus with potential anti-SARS-CoV-2 activity. Gene expression studies were performed in 10 SARS-CoV-2 (−) and 24 SARS-CoV-2 (+) pneumonia patients. A structure-based virtual screen was performed with 10,761 small molecules retrieved from DrugBank, using the GRP78 nucleotide binding domain and substrate binding domain as molecular targets. Results indicated that GRP78 mRNA levels were approximately four times higher in the blood of SARS-CoV-2 (+) versus SARS-CoV-2 (−) pneumonia patients, further suggesting that GRP78 might be a good molecular target to treat Covid-19. In addition, a total of 409 compounds were identified with potential as GRP78 inhibitors. In conclusion, we found preliminary evidence that further proposes GRP78 as a possible molecular target to treat Covid-19 and that many clinically approved drugs bind GRP78 as an off-target effect. We suggest that further work should be urgently carried out to confirm if GRP78 is indeed a good molecular target and if some of those drugs have potential to be repurposed for SARS-CoV-2 antiviral activity.
Highlights
Coronaviruses mainly cause enzootic infections in birds and mammals but in some cases have been capable of crossing the species barrier and infect humans [1]
glucose regulating protein 78 (GRP78) gene expression studies were conducted in Severe Acute Respiratory Syndrome (SARS)-CoV-2 (−) and SARS-CoV-2 (+) pneumonia patients
Our results, together with the ones published by the abovementioned studies, allow to hypothesize that GRP78 may be a receptor for SARS-CoV-2, and a good molecular target to treat Covid-19
Summary
Coronaviruses mainly cause enzootic infections in birds and mammals but in some cases have been capable of crossing the species barrier and infect humans [1]. Since 2002, β-coronaviruses have caused three zoonotic outbreaks [1]. The SARS-CoV-2 emerged as a zoonotic outbreak at the end of 2019, causing a disease named Covid-19 and being responsible for a pandemic within very few months [1]. SARS-CoV-2 is an enveloped virus with a positive-sense, single-stranded RNA genome [2]. This virus enters host cells by receptor-mediated endocytosis [2]. The spike S glycoprotein allows the attachment and virus internalization to the host cell [3], by binding to the host ACE2 receptor [4,5,6,7]. SARS-CoV-2 uses the host cell’s machinery to produce more virus. The new viruses are assembled, enveloped and released from the cells via exocytosis, to infect other cells [9]
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