BMS2047 - Covid-19 Essay-2 PDF

On 11th March 2020 the World Health Organization (WHO) declared the COVID-19 virus outbreak had reached that of global pandemic status. Over the past year the science community has learnt about the effects this novel virus can have on patients and thus considered potential treatments to tackle the v...

On 11th March 2020 the World Health Organization (WHO) declared the COVID-19 virus outbreak had reached that of global pandemic status. Over the past year the science community has learnt about the effects this novel virus can have on patients and thus considered potential treatments to tackle the virus directly, the impact the virus has on our cellular function and the long-term symptoms that can occur. a. After diagnosis with COVID-19 we want to reduce the rate of transmission, identify classes of drugs that could be used and explain a rationale for your first-choice drug. B. Anti-inflammatories are essential tools in treating mild, moderate and severe COVID-19. Discuss how anti- inflammatories can treat COVID-19 by reducing the symptoms and complications. c. Discuss the pathophysiological rationale and mechanism of action of carbamazepine treatment in COVID-19 induced neuropathic pain. A To reduce transmission of COVID- 19, a positive single- stranded RNA, isolation and contact tracing is crucial. With the influence of environmental factors, dissemination of the virus occurs via three routes: person to person; by aerosols and transmission by touch (https://chemistryeurope.onlinelibrary.wiley.com/doi/full/10.1002/cbic.202000595?casa_token=low23mOLMLIA AAAA%3Af2Jo1FlYPIhbKXOQJkhi932px5bobSUBY_rqgl6KRsykFNqvZ_9Y9Js3znubgi9AQqKu6GOGrSdyqpn0g). Potential drug treatments are limited, each of the following options target a different stage of the viral cell cycle; remdesivir (viral entry), favipiravir (replication), and lopinavir and ritonavir (protease inhibitors). First investigated to treat Hepatitis C, Remdesivir (nucleoside analogue) (https://link.springer.com/article/10.1007/s15010-020-01557-7), is seen to be ‘first choice’ due to its ability to interfere with RNA- dependent RNA polymerase (RdRp) to inhibit RNA synthesis and replication, causing a reduction in clinical convalescence and hospital risk (https://link.springer.com/article/10.1007/s15010-020-01557-7). The drug can be taken intravenously (IV) for five days or orally (known as Veklury) for a three- day duration. And its mechanism of a nucleoside analogue is robust against the SARS- CoV2 machinery to infect. Figure 1: Remdesivir......... adapted from https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32094225/ Edited from https://www.asbmb.org/asbmb-today/science/022720/study-sheds-light-on-howa-drug-being-tested-in-co FIGURE LEGEND As displayed in Figure 1, Remdesivir's adenosine triphosphate resembles ATP (as highlighted), a purine nucleotide. Viral RNA polymerases are therefore led to incorporate the P- glycoprotein substrate into replicating viral RNA strands, leading to premature chain termination. Therefore, this antiviral is an adenosine analogue. This idea holds a strong relation to the life cycle of SARSCoV-2, where following endocytosis, the uncoated viral genome will bind to the Endoplasmic Reticulum in the host cell for the subsequent translation of replicase proteins (PP1a and PP1ab) and RdRp. After this, replication and discontinuous transcription will produce the +ssRNA upon assembly of the virions, which will infect through exocytosis (https://chemistryeurope.onlinelibrary.wiley.com/doi/full/10.1002/cbic.202000595?casa_token=low23mOLMLIA AAAA%3Af2Jo1FlYPIhbKXOQJkhi932px5bobSUBY_rqgl6KRsykFNqvZ_9Y9Js3znubgi9AQqKu6GOGrSdyqpn0g. This infection mostly affects respiratory tract epithelial cells, as an example, alveolar type II (AT2) cells found in the alveoli. The onset of the virus begins at the binding of the angiotensinconverting- enzyme 2 (ACE 2) receptors from the host cell, recognized by the S- protein on the surface of the virus (LECTURE NOTES- TUTORIAL); ACE 2 is at high volumes in the epithelium (https://chemistryeurope.onlinelibrary.wiley.com/doi/full/10.1002/cbic.202000595?casa_token=low23mOLMLIAA AAA%3Af2Jo1FlYPIhbKXOQJkhi932px5bobSUBY_rqgl6KRsykFNqvZ_9Y9Js3znubgi9AQqKu6GOGrSdyqpn0g). To aid in the virus’ entry in the lung, endothelial ‘cellular serine protease TMPRSS2’ (https://eur02.safelinks.protection.outlook.com/GetUrlReputation ) is required to cleave peptide bonds of proteins that has a nucleophilic amino acid within its active site (What is TMPRSS2? News-MedicalNews-Medicalhttps://www.news-medical.net › health › What-is-TMPR...). With the administration of Remdesivir, intravenously (likely if patient is hospitalized), the pro-drug is metabolized by cytochrome p450 system and carboxylases (ADME and Pharmacokinetic Properties of Remdesivir: Its Drug...nih.govhttps://pubmed.ncbi.nlm.nih.gov ›...) where p450 which reduces toxicity of drugs to make it easier for the body to excrete. Figure 2: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8308800/ As displayed in Figure 2, the antiviral is known to be converted into different forms before accumulating in the peripheral blood (https://ijpsr.com/bft-article/overview-of-favipiravir-andremdesivir-treatment-for-covid-19/?view=fulltext). Following infusion, the drug is first converted into a alanine metabolite, once diffused though the cellular membrane, and then converted into a nucleoside monophosphate (NMP) through a series of hydrolysis reactions in the cytosol. GS441524 (labelled in Figure 2) becomes hydrophilic after these reactions, so therefore remains inside the infected mononuclear cells (http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8308800/ ; this may be affected by the transporter expression profile in the cell membrane, as other glycoproteins may influx RDV out. Phosphorylation is vital for the antiviral to become its active form as a triphosphate, to assemble the mechanism mentioned before, and terminate transcription. Severe symptoms of this drug were reported as respiratory and organ failure, reduction in red blood cells and platelet count and potential yellowing of the skin. Although there is ambiguity in studies of Remdesivir metabolism, it is seen that intravenous administration of Remdesivir is more favorable than oral, due to its 100% absorption rate (http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8308800/. This route would also ensure compliancy from the patient. RDV will not completely eradicate the virus spreading from person- to- person, as prodrug onto acts in infected cells. In addition, at lower concentrations, the residual virus may still multiply; it has been shown that more than 200mg/ day has been linked to renal dysfunction http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8308800/.