Abstract
Remdesivir is a nucleotide prodrug that is currently undergoing extensive clinical trials for the treatment of COVID-19. The prodrug is metabolized to its active triphosphate form and interferes with the action of RNA-dependent RNA polymerase of SARS-COV-2. Herein, we report the antiviral activity of remdesivir against human coronavirus 229E (HCoV-229E) compared to known anti-HIV agents. These agents included tenofovir (TFV), 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA), alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC), known as nucleoside reverse-transcriptase inhibitors (NRTIs), and a number of 5′-O-fatty acylated anti-HIV nucleoside conjugates. The anti-HIV nucleosides interfere with HIV RNA-dependent DNA polymerase and/or act as chain terminators. Normal human fibroblast lung cells (MRC-5) were used to determine the cytotoxicity of the compounds. The study revealed that remdesivir exhibited an EC50 value of 0.07 µM against HCoV-229E with TC50 of > 2.00 µM against MRC-5 cells. Parent NRTIs were found to be inactive against (HCoV-229E) at tested concentrations. Among all the NRTIs and 5′-O-fatty acyl conjugates of NRTIs, 5′-O-tetradecanoyl ester conjugate of FTC showed modest activity with EC50 and TC50 values of 72.8 µM and 87.5 µM, respectively. These data can be used for the design of potential compounds against other coronaviruses.
Highlights
Human coronavirus 229E (HCoV-229E) is one of the seven known human coronaviruses, which include HCoV-NL63, HCoV-OC43, HCoV-HKU1, Middle East respiratory syndrome (MERS)-CoV, severe acute respiratory syndrome (SARS)-CoV-1, and SARS-CoV-2.HCoV-229E is a member of the genus Alphacoronavirus, which infects humans and bats [1]
Four of the human coronaviruses (HCoV-229E, HCoV-HKU1, HCoV-OC43, and HCoV-NL63) are associated with lower respiratory tract infections, including bronchiolitis and pneumonia [2,3] or upper respiratory tract infections characterized by rhinorrhea, nasal congestion, sore throat, sneezing, and cough that may be associated with acute otitis media or asthma exacerbations [4]
We have previously shown that the conjugation of certain fatty acids to the anti-human immunodeficiency virus (HIV) nucleoside reverse-transcriptase inhibitors (NRTIs), such as FLT, 3TC and FTC, enhanced activity against X4, R5, cell-associated, and/or multi-drug resistant virus when compared with their parent nucleosides [24,25,26,27]
Summary
Human coronavirus 229E (HCoV-229E) is one of the seven known human coronaviruses, which include HCoV-NL63, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1, and SARS-CoV-2.HCoV-229E is a member of the genus Alphacoronavirus, which infects humans and bats [1]. Human coronavirus 229E (HCoV-229E) is one of the seven known human coronaviruses, which include HCoV-NL63, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1, and SARS-CoV-2. Four of the human coronaviruses (HCoV-229E, HCoV-HKU1, HCoV-OC43, and HCoV-NL63) are associated with lower respiratory tract infections, including bronchiolitis and pneumonia [2,3] or upper respiratory tract infections characterized by rhinorrhea, nasal congestion, sore throat, sneezing, and cough that may be associated with acute otitis media or asthma exacerbations [4]. The infection is detected with other respiratory viruses, with the human respiratory syncytial virus (HRSV) [2]. These HCoV related infections may be Molecules 2020, 25, 2343; doi:10.3390/molecules25102343 www.mdpi.com/journal/molecules take several years. Several existing drug and potential drug candidates such as remdesivir and other antiviral agents have been considered to be repurposed as COVID-19 treatments
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