Assis.Prof.Dr.Fatima Adnan Ali Role of Chloroquine in the treatment of COVID-19

Adding Date: 13/05/2020
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Published by: Al-Mustaqbal College Administration
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the viral strain related to Severe acute respiratory syndrome-coronavirus (SARS-CoV 1). It causes coronavirus disease 2019 (COVID-19), which characterized by pulmonary infection in humans. Symptoms ranged from mild to severe illness and death. They may appear 2-14 days after exposure (based on the incubation period of the virus) and include : Fever, Cough and Shortness of breath(1,2).
Human-to-human transmission of SARS-CoV-2 occurs primarily via respiratory droplets from coughs and sneezes within a range of about 1.8 metres (6 ft). Indirect contact via contaminated surfaces is another possible cause of infection(3,4) Viral RNA has also been found in stool samples from infected individuals(5).
The efforts of international health authorities have since focused on rapid diagnosis and isolation of patients as well as the search for therapies able to counter the most severe effects of the disease. In the absence of a known efficient therapy and because of the situation of a public-health emergency, it made sense to investigate the possible effect of chloroquine/hydroxychloroquine against SARS-CoV-2 since this molecule was previously described as a potent inhibitor of most coronaviruses, including SARS-CoV-1. Preliminary trials of chloroquine repurposing in the treatment of COVID-19 in China have been encouraging, leading to several new trials(6).
Structural biology of SARS COV 2
Like other coronaviruses, SARS-CoV-2 has four structural proteins, known as the spike (S) glycoprotein, envelope protein, membrane protein, and nucleocapsid protein. Nucleocapsid holds the RNA genome, and the remaining proteins together create the viral envelope. The spike protein is responsible for allowing the virus to attach to and fuse with the membrane of a host cell (7,8).
Viral Infection Of The Alveolar Epithelium
Coronaviruses are being associated increasingly with severe diseases in the lower respiratory tract. Alveolar epithelial cells are an important target for coronavirus infection in the lung.
The alveolar epithelium consists of two morphologically and functionally distinct cell types. AT1 cells that function in gas exchange and fluid homeostasis. And AT2 that produce surfactant lipids and proteins that keep the alveoli open and contribute to innate defense of the lung.
Infection of AT1 cells can impair gas exchange and removal of fluid from the lung. In addition, infection of AT2 cells can compromise repair of the damaged alveolar epithelium and innate defense of the alveoli (9).
SARS-CoV-2 has sufficient affinity to the membrane receptor angiotensin converting enzyme 2 (ACE2) on the alveolar epithelial cells to use this receptor as a mechanism of cell entry. So the critical step in this attachment between the virus and host cell is binding of S-glycoprotein to the ACE2 receptor on the surface of human cells. Both the S-glycoprotein and ACE2 receptor are known to be extensively glycosylated, i.e. they contain covalently linked complex oligosaccharides called glycans(8,10).

The life cycle of SARS-CoV in host cells
SARS-CoV1 require the presence of sialic acid which are acidic monosaccharides present on host cell transmembrane proteins and they are critical components of ligand recognition, which is associated with subsequent engagement and binding of the virion, via its spike protein, to the receptor ACE2 on the target cell. Then the virion is taken in by endocytosis. Endosome is characterized by low pH, the activation step that occurs in the endosomes at this acidic pH results in fusion of the viral and endosomal membranes leading to the release of the viral SARS-CoV genome into the cytosol. The virus is targeted to the lysosomal compartment where the low pH, along with the action of enzymes, disrupts the viral particle, thus liberating the infectious nucleic acid and, in several cases, enzymes necessary for its replication. Upon transcription and translation, the viral structural and nonstructural proteins and genomic RNA are then assembled into virions, which are subsequently transported via vesicles and released out of the target cell(11).
Chloroquine
Chloroquine and its derivative hydroxychloroquine were drugs used for decades in the treatment and prophylaxis of malaria and are one of the most prescribed drugs worldwide. Hydroxychloroquine has pharmacokinetics and pharmacological activity similar to that of chloroquine except its less toxic (chloroquine can cause a slowing of the heart's rhythm that can potentially lead to fatal complications).
Chloroquine is also utilized in the treatment of autoimmune diseases, in the control of inflammatory processes, and it has broad-spectrum activity against a range of bacterial, fungal and viral infections where it was used in the treatment of SARS-CoV-1 infection and gives good results in the management of COVID 19(12,13).
Mode of antiviral action of chloroquine
Chloroquine has multiple mechanisms of action:
1. Inhibit the biosynthesis of sialic acids. This account for the broad antiviral spectrum of this drug since viruses such as some human coronavirus use sialic acid moieties as receptors.
2. The potent anti-SARS-CoV-1 effects of chloroquine in vitro were considered attributable to a deficit in the glycosylation of a virus cell surface receptor, the angiotensin-converting enzyme 2 (ACE2) so interfere with the binding of S-glycoprotein to the ACE2 receptor .
3. Chloroquine can also impair early stage of virus replication by increasing the pH of the endosome, so it will inhibit virus–endosome fusion, replication cycle and impair the proper maturation of viral protein.
4. this drug could act indirectly through reducing the production of pro-inflammatory cytokines (like IL-1, IL-6 and TNFα ) which usually elevated during SARS-CoV 1and 2 infections, and/or by activating anti-SARS-CoV-2 CD8+ T-cells (6,14).
Conclusion
Since SARS-CoV-2 was found to utilise the same cell surface receptor ACE2 as SARS-CoV-1, it may be hypothesised that chloroquine also interferes with ACE2 receptor glycosylation thus preventing SARS-CoV-2 binding to target cells. Chloroquine also has been shown to be capable of inhibiting the in vitro replication of several coronaviruses. Recent publications support the hypothesis that chloroquine can improve the clinical outcome of patients infected by SARS-CoV-2. The multiple molecular mechanisms by which chloroquine can achieve such results remain to be further explored.



References
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12. Awadhesh Kumar Singh,a, Akriti Singh,b Altamash Shaikh,c Ritu Singh,a and Anoop Misra (2020). Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes Metab Syndr.; 14(3): 241–246.
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14. B. Gay, E. Bernard, M. Solignat, N. Chazal, C. Devaux, L. BriantpH-dependent entry of Chikungunya virus into Aedes albopictus cells Infect Genet Evol, 12 (2012), pp. 1275-1281.




Assis.Prof.Dr.Fatima Adnan Ali