Summary: Remdesivir, originally developed to treat Ebola and now rapidly entering clinical trials for COVID-19, effectively blocks the coronavirus replication machinery. The drug masquerades as a viral building block, becomes repeatedly incorporated by the viral polymerase, and ultimately halts replication of SARS-CoV-2.
Source: University of Alberta
Researchers at the University of Alberta report that remdesivir potently inhibits the replication mechanism of the coronavirus responsible for COVID-19, according to new findings published in the Journal of Biological Chemistry.
The new study builds on earlier work from the same laboratory published in late February, which showed how remdesivir acted against the related Middle East Respiratory Syndrome (MERS) coronavirus.
“We were hopeful that the results would be similar for SARS-CoV-2,” said Matthias Götte, chair of medical microbiology and immunology at the University of Alberta.
“Our experiments produced results nearly identical to those we observed with MERS, demonstrating that remdesivir is a highly potent inhibitor of coronavirus polymerases.”
Götte’s paper explains in molecular detail how remdesivir, developed in 2014 during the Ebola outbreak, interferes with viral replication. He compares the polymerase to the virus’s engine—the enzyme responsible for copying the virus’s RNA genome.
“Targeting the polymerase is a logical antiviral strategy because if the polymerase is blocked, the virus cannot replicate and spread,” Götte said.
The laboratory’s biochemical analyses reveal that remdesivir acts by mimicking the natural nucleotide building blocks used by the viral polymerase.
“Coronavirus polymerases are surprisingly permissive and make mistakes, so the drug’s nucleotide form is incorporated into the growing RNA strand. After incorporation, repeated additions lead to stalled replication and termination of RNA synthesis,” Götte explained.
Based on these laboratory results and prior studies in cells and animal models, the team classifies remdesivir as a direct-acting antiviral (DAA) against SARS-CoV-2. The term DAA is used for drugs that interfere directly with essential viral enzymes or steps in the replication cycle, similar to newer hepatitis C virus therapies.
These mechanistic findings support the rationale for ongoing clinical trials testing remdesivir in hospitalized COVID-19 patients worldwide. However, Götte emphasized that laboratory potency does not automatically predict clinical benefit.
“Laboratory studies provide crucial insights, but we must await data from randomized clinical trials to understand how the drug performs in patients,” he said. His research received funding from the Canadian Institutes of Health Research, Alberta’s Major Innovation Fund, and Gilead Sciences, the manufacturer of remdesivir.
Götte’s lab shifted its focus several years ago from HIV and hepatitis C virus research to viruses that pose the greatest epidemic threat. In 2015, the World Health Organization identified several high-risk pathogens—Ebola, Lassa and coronaviruses among them—and the group’s expertise in viral polymerases positioned them to respond quickly to SARS-CoV-2.
“Our laboratory’s long-standing focus on viral polymerases meant we were prepared to study SARS-CoV-2 quickly,” Götte said. He plans to apply the same experimental toolkit to evaluate other promising antiviral candidates.
Götte expressed optimism that the unprecedented global research effort and high levels of collaboration will yield one or more effective COVID-19 treatments.
“We are desperate for effective therapies, but we still must maintain rigorous standards for any treatment advanced into clinical trials,” he said.
Remdesivir is among several therapies being prioritized by the World Health Organization for accelerated clinical testing in hospitalized COVID-19 patients across multiple countries, including Canada. Götte noted that preliminary clinical trial results could emerge within months, depending on trial enrollment and design.
He also reflected on missed opportunities: antiviral compounds identified during the 2003 SARS outbreak were not fully developed into approved treatments, in part because drug development demands large investments. “This time we must push across the finish line,” Götte said. “While drug development can cost billions, in the context of a global pandemic those costs are small compared to the human and economic toll of the disease.”
About this COVID-19 research article
Source:
University of Alberta
Media Contacts:
Ross Neitz – University of Alberta
Image Source:
The image is in the public domain.
Original Research: Closed access
“Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency”, by Matthias Götte et al. Journal of Biological Chemistry, doi: 10.1074/jbc.RA120.013679.
Abstract
Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency
Effective therapies for COVID-19 are urgently needed. SARS-CoV-2 replication depends on the viral RNA-dependent RNA polymerase (RdRp), the presumed target of the investigational nucleotide analogue remdesivir (RDV). RDV displays broad-spectrum activity against RNA viruses, and prior studies with Ebola and MERS polymerases suggested delayed chain termination as RDV’s mechanism. In this study, active SARS-CoV-2 RdRp composed of non-structural proteins nsp12 and nsp8 was expressed and purified. Enzyme kinetics show efficient incorporation of the active triphosphate form of remdesivir (RDV-TP) into nascent RNA, with incorporation at position i causing termination at i+3. Nearly identical results were obtained for SARS-CoV and MERS-CoV polymerases. RDV-TP shows high selectivity versus the natural nucleotide ATP, a distinction not shared by several other nucleotide analogues such as 2’-C–methylated compounds and broad-acting antivirals like favipiravir and ribavirin. RDV-TP was incorporated less efficiently by the more distantly related Lassa virus polymerase, and no termination was observed there, supporting RDV’s target specificity. Collectively, these results refine the mechanism by which remdesivir inhibits coronavirus RNA synthesis and define it as a direct-acting antiviral.
Feel free to share this coronavirus news.