PHR 213: Pharmacology-I

Assignment on

Potential drug candidates to treat COVID-19

Submitted To :

Md. Samiul Alam Rajib

Senior Lecturer

Department of Pharmacy

Brac University

Submitted By:

Samarah Arjumand

ID: 18146068

Section: 02
 INDEX:

Topic Page No.

Introduction 01

Remdesivir (Therapeutic class, Structure, 01-02

Mechanism of action)

Favipiravir (Therapeutic class, Structure, 02-03

Mechanism of action)

Tocilizumab (Therapeutic class, Structure, 03-04

Mechanism of action)

Azithromycin (Therapeutic class, Structure, 04-05

Mechanism of action)

Conclusion 05

Reference 05
Coronavirus Disease 2019 (CoVID 19) is an infectious disease that was first identified and spread
in Wuhan, China and has caused a global pandemic now. It was found to be caused by a novel
coronavirus which was named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-
2). The symptoms of this infection range from fever, chill, sore throat, muscle pain, loss of smell
to pneumonia in extreme cases. Up till 4th of June, total number of worldwide cases was 6636148.
389710 people have died and recovered cases are 3201599. To combat this situation, the World
Health Organization (WHO) has launched a worldwide project called the “Solidarity trial for
treatments” to find proper, proven and effective treatment for this viral infection. It was announced
on March 18, 2020. Till now, a large number of drugs are being investigated from direct acting
antiviral drugs to drugs for managing symptoms and complications like- Immunomodulators,
Immunotherapies, Antibody-directed therapies and even antibiotics.

Remdesivir:

It is an investigational broad-spectrum antiviral medicine which is actually a nucleotide analog

prodrug. It is given intravenously (IV) to directly inhibit viral RNA synthesis.

Therapeutic class: Antiviral drug.

Structure:

Figure: Structure of Remdesivir

Mechanism of action: Remdesivir is a prodrug of nucleotide analog (GS-441524) which is

metabolized into an adenosine triphosphate analog. This mimic of adenosine is mistakenly used
by the viral RNA-dependent RNA polymerase (RdRp) in the transcription process of child viral
RNA production. The process is then interrupted and stopped midway. In SARS-CoV, MERS-
CoV and SARS-CoV-2, this halt occurs by delayed chain termination as it occurs three nucleotide
after this adenosine analog incorporation. For some viruses, the analog even can pause the RdRp
itself.
 Figure: Mechanism of action of Remdesivir against SARS-CoV-2

Along with that, it can interfere with the proofreading ability of 3’-5’ exoribonuclease(ExoN) if a
mutant less effective ExoN is incorporated with remdesivir and thus more antiviral activity is seen.

Favipiravir: It is a Japan approved antiviral drug for influenza which selectively hindering RNA
polymerase crucial for viral replication. It is available both in oral and intravenous form.

Therapeutic class: Antiviral drug.

Structure:

Figure: Structure of Favipiravir

Mechanism of action:

Favipiravir is a prodrug that metabolizes into the active favipiravir-ribofuranosyl-5’-triphosphate

(favipiravir-RTP) through intracellular phosphorylation and ribosylation. It works as a modified
pyrazine analog and is competent with rather purine nucleosides. It works similarly as remdesivir
in halting the child RNA transcription process by RdRp or pausing the RdRp. According to another
research, it causes lethal RNA mutations producing an ineffective viral RNA. Along with that, as
RdRp is related to the replication of a good number of RNA viruses, by inhibiting its activity it
can show broad-spectrum antiviral activity.

Tocilizumab: It is an immunosuppressive drug that is actually a humanized monoclonal antibody

for blocking the interleukin receptor (IL-6R). It is mainly used to manage rheumatoid arthritis and
systemic juvenile idiopathic arthritis. In severe CoVid-19 patients, due to over activation of the
immune system against the virus, excessive amount of proinflammatory cytokines are synthesized
leading to a state called ‘cytokine storm’. It leads to blood-gas exchange dysfunction (acute
respiratory distress syndrome), pulmonary fibrosis that makes sufficient oxygenation a problem
and organ failure which can be fatal.

In the cytokine storm, IL-6 and granulocyte macrophage colony stimulating factor (GM-CSF) is
predominant. Again, GM-CSF lead to additional IL-6 production. That’s why, by blocking
receptors for IL-6, this cytokine storm can be managed.

Therapeutic Class: Disease modifying antirheumatic drug.

Structure:

Figure: Structure of Tocilizumab (IL-6 inhibitor)

Mechanism of action: For controlling over activation of interleukin-6 (IL-6), IL-6 inhibitors (in
this case, Tocilizumab) are used. Tocilizumab competes with endogenous IL-6 and binds itself to
the IL-6 receptors including both soluble and membrane bound IL-6 receptors. Thus, it prevents
IL-6 from over activating, showing pro-inflammatory activity and creating a fatal cytokine storm.
 Figure: How Tocilizumab blocks IL-6R

Azithromycin: It is a broad-spectrum macrolide antibiotic which is generally used for respiratory,

enteric and genitourinary infections. Though Sars-CoV-2 is a virus, azithromycin helps in the
treatment process by acting against secondary bacterial infection caused post a severe viral
infection. Along with that, it works as an immunomodulatory drug providing anti-inflammatory
activity.

Therapeutic activity: Broad spectrum antibiotic.

Stucture:

Figure: Structure of Azithromycin.

Mechanism of action: In an in vitro study, it was found that azithromycin leads to pH increase in
trans-Golgi network of the primary bronchial epithelial cell which causes heavy interference in the
viral protein packaging of its replication process. It can also change the glycosylation of the
angiotensin-converting enzyme 2 receptor where SARS-CoV-2 binds making it non-susceptible
in the process. Another result showed, azithromycin can reduce furin enzyme level which is
potentially present in the spike protein of the virus preventing its entry to the host cell.
Azithromycin shows its antibacterial ability by binding to the 50S ribosome of the bacteria making
it unavailable for further RNA transcription and thus its replication process.
Macrolide antibiotics again can reduce pro-inflammatory cytokines. Azithromycin specially can
reduce IL_8 secretion. Thus, it can help in reducing cytokine storms and provide anti-inflammatory
activity.

These are the few drugs that are being most talked about and still accepted. In spite of being seen
as promising first, antimalarial drug hydroxychloroquine is off from the ‘Solidarity trial’ program
now due to its potential fatal side effects. Along with that, other antiviral drugs like Ivermectin,
Lopinavir/ritonavir, umifenovir etc. are also in trials. Prophylactic and therapeutic anticoagulants
are also being used to treat consequential Disseminated Intravascular coagulopathy. Plasma
therapy is also being considered a potential good option in the treatment process. Hopefully, an
effective treatment will be discovered through all these trials in the near time soon.

References:

https://emedicine.medscape.com/article/2500114-overview

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713175/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195979/

https://pubchem.ncbi.nlm.nih.gov/compound/Remdesivir

https://pubchem.ncbi.nlm.nih.gov/compound/Favipiravir#section=Metabolism-Metabolites

https://www.cebm.net/covid-19/what-is-the-evidence-for-use-of-macrolide-antobiotics-for-
treatmetnof-covid-19/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653965/#:~:text=Azithromycin%20is%20a%2
0broad%2Dspectrum,sexually%20transmitted%20and%20enteric%20infections.

https://www.goodrx.com/blog/coronavirus-treatments-on-the-way/#remdesivir

https://emedicine.medscape.com/article/2500114-treatment#d10

https://vimeo.com/422769056

https://www.youtube.com/watch?v=7EmCBqEBmfY

https://www.cebm.net/covid-19/what-is-the-evidence-for-use-of-macrolide-antobiotics-for-
treatmetnof-covid-19/