The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus

Abstract

Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including SARS-CoV and Middle East respiratory syndrome (MERS-CoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps).Here, we co-expressed the MERS-CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS-CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogues. Once incorporated at position i, the inhibitor caused RNA synthesis arrest at position i+3. Hence, https://www.jbc.org/cgi/

The epidemiology, diagnosis and treatment of COVID-19

“…In a rhesus macaque model of MERS-CoV infection, prophylactic remdesivir treatment was initiated 24 h prior to inoculation, and MERS-CoV did not induce clinical disease and did not replicate in respiratory tissues, thus preventing the formation of lung lesions [51] . In cell-based assays, the triphosphate form of remdesivir incorporated at position i, and RNA chain termination was delayed, which explained the high potency of remdesivir against RNA [52] . Remdesivir was used to treat the first case of COVID-19 infection in the United States: the patient's clinical condition improved after only one day of remdesivir treatment [53] .…”

Coronavirus Disease (COVID-19): A primer for emergency physicians

“…4,46 Remdesivir has demonstrated activity against MERS-CoV and SARS-Cov in vitro and animal models. 82,83 An in vitro study found that remdesivir and chloroquine inhibit viral infection, but further study is required. 84,85 Results from a single study of over 100 COVID-19 patients found chloroquine was superior to control in reducing pneumonia exacerbation, improving imaging findings and virus-negative conversion, and shortening the course of the disease.…”

The SARS-CoV-2 outbreak from a one health perspective

“…In the light of the One Health concept, control of this emerging virus requires the reduction of the viral shedding to the environment from the main reservoirs, for animal-person transmission and from humans for person-person transmission [35]. Based on the previous experience from the other emerging diseases, particularly SARS-CoV and influenza viruses, avoiding the mixing of various species of animals, birds, and mammals, is highly suggested [51,65,66]. This strategy will minimize the possibility of recombination among not only these pathogens but also for other common pathogens in the near future.…”

“…The regular monitoring of various coronaviruses, especially in various species of bats, animals, and birds on the genomic level, is highly recommended. Some studies suggested the most human coronaviruses; including SARS-CoV, MERS-CoV, HCoV-229E, and HCoV-NL63 originated from bats [25,65]. This highlights the mandate for continuous monitoring of the coronaviruses population in bats as an alarm to the emergence of new novel coronaviruses in the future.…”

“…This approach diminished the ability of the virus to copy its genome; thus, the replication cycle J o u r n a l P r e -p r o o f may be interrupted. This compound gave promising results in the cell culture model, which requires further testing in laboratory animals before the clinical trials [65].…”