In a pandemic like Covid-19 the urgent need excludes the development of new drugs, “conventional drug in new use” becomes a viable solution. In the United States, the first patient with COVID-19 has shown significant improvement in clinical symptoms within 24 h of treatment with remdesivir. This case has convinced the public that remdesivir could become a new “specific drug” for COVID-19. The recent paper of Cao et al. starts from the structure, immunogenicity, and pathogenesis of infection of the SARS-CoV-2, and then analyzes the feasibility of conducting trials and putting into clinical use of COVID-19 from the pharmacological characteristics and successful cases of remdesivir.
Fig. 1 SARS-CoV-2 invasion process and how remdesivir works
1 SARS-CoV-2 enters target cells by binding the S protein to the ACE2 receptor on the cell surface; 2 Remdeivir, the nucleotide analogues, act as RdRp inhibitors, can provide a scheme for blocking RNA replication; 3 Once remdesivir added into the growing chain (i position), it cannot cause an immediate stop. On the contrary, it will continue to extend three more nucleotides down to stop the strand at (i + 3) position; 4 Remdesivir triphosphate cannot be removed by nsp14-ExoN.
Remdesivir (GS-5734) is a nucleoside analogues drug (Fig. 3B) with extensive antiviral activity and effective treatment of lethal Ebola and Nipah virus infections in nonhuman primates. As an RNA-dependent RNA polymerase (RdRp) inhibitor, it can inhibit the replication of multiple coronaviruses in respiratory epithelial cells.
Pharmacokinetic experiments in cynomolgus monkeys showed the first-pass effect of oral remdesivir resulted in a low bioavailability of the drug. Intramuscular injection of 3 mg/kg had a 50% survival rate compared with the control group. Administering intravenously at a dose of 10 mg/kg, remdesivir rapidly decomposed into the original drug (nucleoside phosphate) in rhesus monkeys. Within 2 h, remdesivir quickly distributed in peripheral blood mononuclear cells, and soon afterwards activated to nucleoside triphosphate to reach a peak, with a survival rate of 100%.
The paper describes the previous animal studies and clinical trials on remdesivir application against Ebola virus, the successful cases of remdesivir in treating Covid-19 and the rationale for clinical trials going on.
“On February 24, the WHO cast a vote of confidence for Gilead Sciences’ experimental antiviral drug, remdesivir, indicating that remdesivir has great potential and may be the best candidate for the treatment of COVID-19. Whatever the progress of the clinical trials is, we are expecting that the clinical trials of remdesivir, a starring drug, would bring outstanding breakthroughs to the treatment of COVID-19, or more promisingly, other virus infection in the future.”
Yu-chen Caoa,1, Qi-xin Denga,1, Shi-xue Daib (2020) Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: An evaluation of the evidence. Travel Medicine and Infectious Disease 101647 (in press) https://doi.org/10.1016/j.tmaid.2020.101647