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Mechanism of action revealed for remdesivir, potential coronavirus drug

Researchers have demonstrated how the drug known as remdesivir works, presenting the viral RNA polymerase of coronaviruses as a target for these conditions.

Coronavirus cells

A team of academic and industry researchers has reported new findings on how exactly an investigational antiviral drug stops coronaviruses. The paper was published the same day that the US National Institutes of Health (NIH) announced that the drug in question, remdesivir, is being used in the country’s first clinical trial of an experimental treatment for COVID-19, the illness caused by the SARS-CoV-2 virus.

Previous research in cell cultures and animal models has shown that remdesivir can block replication of a variety of coronaviruses, but until now it has not been clear how it does so. The researchers, from the University of Alberta, US, and Gilead, studied the drug’s effects on the coronavirus that causes Middle East Respiratory Syndrome (MERS). They found that remdesivir blocks a particular enzyme that is required for viral replication. 

Coronaviruses replicate by copying their genetic material using an enzyme known as the RNA-dependent RNA polymerase. Until now, it has been difficult to get the polymerase complex that contains multiple proteins to work in a test tube.

“It hasn’t been easy to work with these viral polymerases,” Matthias Götte, a virologist and professor at the University of Alberta who led the study. He explained that this has slowed research into new drugs’ function. 

Using polymerase enzymes from the coronavirus that causes MERS, scientists in Götte’s lab found that the enzymes can incorporate remdesivir, which resembles an RNA building block, into new RNA strands. Shortly after adding remdesivir, the enzyme stops being able to add more RNA subunits. This halts genome replication.

The scientists hypothesise that this might happen because RNA containing remdesivir takes on a strange shape that does not fit into the enzyme. To find out for certain, they would need to collect structural data on the enzyme and newly synthesised RNA. Such data could also help researchers design future drugs to have even greater activity against the polymerase. They suggest the viral RNA polymerase of coronaviruses as a target.

The study was published in the Journal of Biological Chemistry.

14 responses to “Mechanism of action revealed for remdesivir, potential coronavirus drug”

  1. Why do some patients show no symptoms at all??? WHY? Is it because their body possess an abundance of certain enzymes that inhibit virus replication? What is that enzyme?

    • Razia Jafri says:

      asymptomatic infection can be seen by 2 mechanisms
      1. due to variability in receptor gene expression which may vary between individuals as well as between cells, for COVID 19 receptor is ACE2 see below
      ACE2provided by HGNC
      Official Full Name
      angiotensin I converting enzyme 2provided by HGNC
      Primary source
      HGNC:HGNC:13557
      See related
      Ensembl:ENSG00000130234 MIM:300335
      Gene type
      protein coding
      RefSeq status
      REVIEWED
      Organism
      Homo sapiens
      Lineage
      Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
      Also known as
      ACEH
      Summary
      The protein encoded by this gene belongs to the angiotensin-converting enzyme family of dipeptidyl carboxydipeptidases and has considerable homology to human angiotensin 1 converting enzyme. This secreted protein catalyzes the cleavage of angiotensin I into angiotensin 1-9, and angiotensin II into the vasodilator angiotensin 1-7. The organ- and cell-specific expression of this gene suggests that it may play a role in the regulation of cardiovascular and renal function, as well as fertility. In addition, the encoded protein is a functional receptor for the spike glycoprotein of the human coronavirus HCoV-NL63 and the human severe acute respiratory syndrome coronaviruses, SARS-CoV and SARS-CoV-2 (COVID-19 virus). [provided by RefSeq, Mar 2020]
      Expression
      Biased expression in small intestine (RPKM 93.7), duodenum (RPKM 69.0) and 5 other tissues See more

      The other reason for severity is underlying diseases, people with chronic lung disease do not have much functional cell reserves and when cells are infected their function declines rapidly

      • B.D. Uhal says:

        I’ve worked with ACE-2 in the lungs at Michigan State University for ~16years. Many people give the explanation you did, but there is NO EVIDENCE to support your explanation. Lots of people are looking, and I’m reviewing many of those studies, but…its not so clear. Other factors may explain it!!

        • Jose Castellanos says:

          I have a belief that some acids do not allow Covid-19 to attack playing a potential mechanism of defense. Regards.

    • carol miller says:

      May likely be that the functioning of the immune system is genetically determined. Persons who perish from this virus do so because their immune systems over-react, and produce a cytokine storm, which ultimately causes organ failure.

      This faulty over-reaction of the immune system is most notable in the elderly, but the genetic factor may be paramount in other individual cases.

    • mike says:

      You have to understand that it is the immune system that causes the symtoms, not the virus itself. Because of that, they can vary greatly between the infected.

  2. Ron Wetherall Pharm says:

    Based on the comments of Razia Jafri, what effect would occur to patients on ACE inhibitors ?

  3. Ron Wetherall says:

    What effect would occur on patients on ACE inhibitors who are exposed to Corona virus 19?

  4. Edward Blonz says:

    Important to examine the data while controlling for ABO blood type. There are data suggesting that the anti-A antibody, found in those with type O and B, may react with the SARS-Cov-2 spike protein and denigrate the viral replication process. Need to control for this variable in all studies of potential meds.

  5. Milan smolko md says:

    What about ACE2 receptor blockers like Cozaar do they block covid19 attachment

  6. John Ordille says:

    Is anybody looking at the PLA-2 which all of these viruses possess? Hydroxychloroquine has PLA-2 blocker properties and that is why it is partially effective. The use of a PLA-2 inhibitor may also reduce the severety of the symptoms before the virus reaches the lungs. The mechanism is similar to what is being disussed here.

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