Sushant Kumar, IISc
SARS-CoV-2 virus, the cause of the COVID-19 pandemic, has resulted in a large number of infections and deaths leading to a global crisis. Remdesivir is one of the few drugs currently used in COVID-19 treatment, with a modest benefit. It blocks viral multiplication, but how exactly it stalls the SARS-CoV2 virus was unclear. The current study provides the necessary details.
A virus multiplies rapidly in host cells, which involves making thousands of copies of the viral genetic material. In the case of SARS-CoV-2, the genetic material consists of RNA (ribonucleic acid). RNA is made up of four chemicals that form the building blocks called nucleosides and are abbreviated as A, U, G and C. These four are arranged in a particular order, just like the beads of a necklace. A viral enzyme called RNA-dependent RNA polymerase (RdRp) makes new copies of the RNA by stringing together the A, U, G and C in the exact same order as in the original viral RNA that infects the host cell. If the RdRp is blocked, then the virus cannot replicate. Due to the vital role of RdRp in the coronavirus life cycle, it is an attractive target for anti-covid drugs (1). Remdesivir mimics the A nucleoside, which is key to its ability to block viral RNA copying. Remdesivir is administered in an inactive form called a prodrug that gets converted to an active form inside the body (2).
A recent study by Eric Xu and colleagues from China, sheds light on the details of how Remdesivir blocks SARS-CoV-2 RNA copying process (3). They used a state-of-the-art microscope called the cryo-Electron Microscope, which uses electron beams to take thousands of 2D photographs of samples that are then computationally combined to get a 3D image. Eric Xu and colleagues used this technique to study the RdRp enzyme bound to Remdesivir to see how it stops the RNA copying process. The fine, molecule-level details of RdRp shows the active part of Remdesivir attached to the growing end of the new RNA copy. This corroborates the understanding that (i) RdRp recognizes the active form of Remdesivir and (ii) given its chemical similarity to nucleosides, RdRp uses Remdesivir in place of natural nucleosides while copying RNA. Incorporation of Remdesivir in the RNA prevents addition of further nucleosides, which stalls the process of copying viral RNA. The lack of new RNA copies ultimately halts viral multiplication. Remdesivir can potentially be used as a broad-spectrum antiviral drug i.e. an antiviral drug against several viruses. While the study reasserts Remdesivir’s molecular mechanism as an antiviral, its use in treating COVID-19 infections would require extensive testing and clinical trials.
Figure Legend. The structural differences in Remdesivir that is important for its function as a drug are highlighted (left). Remdesivir (yellow) binds to the growing end of the viral RNA chain and terminates replication (middle & right).
1. Gordon, C.J., Tchesnokov, E.P., Woolner, E., Perry, J.K., Feng, J.Y., Porter, D.P. and Gotte, M. (2020) Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency(link is external). J Biol Chem, 295, 6785-6797.
2. Siegel, D., Hui, H.C., Doerffler, E., Clarke, M.O., Chun, K., Zhang, L., Neville, S., Carra, E., Lew, W., Ross, B. et al. (2017) Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses(link is external). J Med Chem, 60, 1648-1661.
3. Yin, W., Mao, C., Luan, X., Shen, D.D., Shen, Q., Su, H., Wang, X., Zhou, F., Zhao, W., Gao, M. et al. (2020) Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by Remdesivir.(link is external) Science, 368, 1499-1504.
[Last updated 24 July 2020 ]