User talk:Daniel Hausaman
From Proteopedia
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Use of Remdesivir as a treatment for COVID-19
Introduction
Remdesivir is a drug that was initially developed for use against Ebola, and has shown to be effective against coronaviruses such as SARS-CoV, MERS-CoV, SARS-CoV-2. SARS-CoV-2 is the virus that is responsible for the disease COVID-19 which is a respiratory disease that can inflict severe damage to multiple major organs including the heart, brain and lungs. SARS-Cov2 relies upon RNA-dependent RNA polymerase (RdRp) to replicate the viral genetic material. Drugs such as nucleoside analogues can be used to inhibit this enzyme and stop viral replication. Remdesivir initially labeled GS-5734 is an adenosine triphosphate analogue, used as a broad-spectrum antiviral drug meaning it can be used to inhibit a wide range of viruses that rely upon RNA-dependent RNA polymerase for genomic replication.
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Structure
On the right-hand side shows the 3D structure of nsp12-nsp7-nsp8 complex also known as the RdRp bound to the template-primer RNA and the triphosphate form of remdesivir which is highlighted in blue to view remdesivir bound to the protein complex
Mechanism
Once administered remdesivir requires metabolic activation, this takes place after the drug diffuses into a cell. Phosphoamidase (HINT1) and esterases CES1 and CTSA transform remdesivir into GS-441524 mono-phosphate. This is then phosphorylated again to produce the active triphosphate analog.
Remdeisvir is a polymerase inhibitor, there are 2 main categories for polymerase inhibitors these are known as nucleoside analogues and allosteric inhibitors. Nucleoside analogues resemble viral building blocks such as Adenosine triphosphate. One of the main ways this inhibits viral replication is because of competitive inhibition between the nucleoside analogue and the viral RNA. To view the RNA highlighted in red viral replication can also be reduced by the incorporation of incorrect nucleotides into the viral genome this can result in chain termination which is initiated by the formation of a phosphodiester bond between the 3′ hydroxyl group of Remdesivir triphosphate and the next nucleotide resulting in the termination of the viral RNA synthesis at the position of 3 nucleotides downstream
Structural highlights
Structure
On the right-hand side shows the 3D structure of nsp12-nsp7-nsp8 complex bound to the template-primer RNA and the triphosphate form of remdesivir which is highlighted in blue to view remdesivir bound to the protein complex
