Repurposing FDA-approved drugs for SARS-CoV-2 through an ELISA-based screening for the inhibition of RBD/ACE2 interactio
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Protein & Cell
LETTER
Dear Editor, The ongoing coronavirus disease 2019 (COVID-19) global pandemic is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which instigates severe and often fatal symptoms. As of September 4th, 2020, more than 26 million cases of COVID-19 and almost 900,000 deaths have been reported to WHO. Based on Kissler and colleagues’ modeled projections of future viral transmission scenarios, a resurgence in SARS-CoV-2 could occur over the next five years (Kissler et al., 2020). Research and clinical trials are underway to develop vaccines and treatments for COVID-19, but there are currently no specific vaccines or treatments for COVID-19 (www.who.int), and therapeutic and prophylactic interventions are urgently needed to combat the outbreak of SARS-CoV-2. Of particular importance is the identification of drugs which are effective, less-intrusive, most socioeconomic, and ready-touse. SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells through interaction between the receptor binding domain (RBD) of viral spike protein and its ACE2 receptor on host cells. It has been proposed that inhibition of this interaction represents a particularly attractive target for the development of treatments for COVID-19 (Shi et al., 2020). Here we developed an ELISA-based high-throughput screening scheme to identify drugs capable of disrupting the interaction between the SARS-CoV-2 RBD and human ACE2 (hACE2). Considering the fact that drug development is time consuming and extremely expensive, we have adopted a strategic approach involving the repurposed use of clinically approved drugs. We first established and optimized our ELISA assay with biotin labeled RBD, and 5 ng/ mL of RBD was used for drug screening (Fig. S1A). A library composed of 958 FDA-approved drugs was screened and five drugs, N-acetylcysteine (NAC), tiopronin (TPR), verteporfin (VP), calcitriol and racecadotril, were identified to inhibit RBD/ACE2 interaction at both low and high concentrations selected (Fig. S1B and S1C). Verteporfin (VP), a benzoporphyrin derivative, is a medication used as photosensitizer to eliminate the abnormal
© The Author(s) 2020
blood vessels, and also used off-label for the treatment of central serous retinopathy. VP has been reported to interact with ACE2 (Gu et al., 2020). Indeed, we found that incubation of VP with ACE2 for 1h before addition of RBD could significantly decrease the half-maximal effective concentration (EC50) from 400.3 nmol/L to 1.1 nmol/L, calculated from ELISA based inhibition curve (Fig. 1A and 1B). Calcitriol, an active form of vitamin D3, mildly inhibited RBD/ACE2 interaction (Fig. S2). Several studies have suggested a link between vitamin D deficiency and poor recovery from COVID-19 (Grant et al., 2020; Mitchell, 2020; Zemb et al., 2020). At least 9 clinical trials concerning the use of vitamin D alone or combination with other drugs for prevention and treatment of COVID-19 are ongoing, thus our data support these clinical trials. Racecadotril, an e
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