Initially, chloroquine in the year 1934 was developed as an anti malarial drug. In the year 1946, hydroxychloroquine was developed as an analog of chloroquine. These antimalarial drugs started to gain recognization shortly after the global spread of SARS-CoV-2 virus in 2020. Which got everyone confused as to how these drugs could potentially be used against the corona virus. Let us check it out.
TIMELINE IN COVID-19: As of March 2020, many countries initially consumed chloroquine/hydroxychloroquine for the treatment of covid infected patients, without a formal clinical trial.April to June 2020 Emergency use authorization started in the USA.
Although on 24 April 2020, FDA published a caution using the drug for covid 19 "outside of a hospital or a clinical trial" and cited the risk of "serious heart rhythm problem."
"FDA cautions against the use of hydroxychloroquine/chloroquine for covid -19 treatment outside of hospital setting or a clinical trial due to risk of a heart rhythm problem."After advisories from WHOs solidarity trial & UKs RECOVERY TRIAL on hydroxychloroquine as a possible covid-19 treatment was withdrawn.
Following this USFDA on June 15, 2020, revoked the emergency use authorization (EUA) that allowed chloroquine phosphate and hydroxylchloroquine sulfate to be used to treat certain hospitalized patients with covid-19 when a clinical trial was unavailable or participation in a clinical trial was not feasible and stated it "unlikely to be effective in the treatment of covid-19 for authorized use in EUA." Having serious side effects & other potential risks.NIH (National Institute of Health) on around 9 Oct. 2020 issued treatment guidelines recommending against the use of hydroxychloroquine for covid-19 except as part of a clinical trial.
CQ/HCQ works against SARS-CoV-2 virus by following three mechanisms:
1. CQ/ HCQ BLOCKS ENDOCYTOSIS:
* The SARS-CoV-2 virus has a spike (S) protein on its surface. This plays a major role in receptor recognization and the cell membrane fusion process.
* Out of the 2 subunits of S-spike, the S1 subunit - contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2 on the host cell.
* When it binds to the ACE-2 receptor it is endocytosed in the cell into the endosome.
* Brought into the cell by that small endosome, will eventually transverse through the cytosol infused to the lysosome.
* Now that the virus enters the lysosome and accesses it which allows the virus to infect the host cell.
* CQ/HCQ blocks this process by entering into the cell because of its lipophilic nature, the drugs enter into the endosomes and lysosomes.
* As the drugs are weak bases, they alkalinize the endosome & lysosomes.
* Thus it increases the pH of the above mention cell organelles, preventing them from being acidified as per their normal nature & functioning. Hence, makes them dysfunctional.
* Due to the alkanisation of endosomes & lysosomes, endocytosis ( the process of bringing the virus into the cells) is inhibited and infusion of endosomes & lysosomes is also stopped.
2. CQ/HCQ a ZINC IONOPHORE:
* Zinc regulates antiviral and antibacterial immunity including inflammatory responses. It is essential for the function of various enzymes & transcriptional factors.
* Increased intracellular zinc concentration impairs the replication process of RNA viruses. * CQ /HCQ allows the entry of zinc into a cell. Without help, zinc cannot enter the cell as it essentially bounces off the cell membrane.
* CQ/ HCQ guides it through the cell membrane allowing zinc to enter into the cell.
* This is vital as zinc inhibits coronavirus RNA polymerase activity & zinc ionophores stops the replication of the virus.
* Normally when a virus enters a cell specifically an RNA virus there is an RNA-dependent RNA polymerase (RdRp) that essentially makes viral RNA and helps in viral replication.
* However, when there is CQ/HCQ & zinc around they can cross over the plasma membrane together. So here, the CQ/HCQ acts as a zinc ionophore allowing zinc & the drug to enter the cell. In addition to the effect of CQ on lysosomes.
* Once the zinc has entered, the concentration of zinc in cytosol increases exponentially. This in turn inhibits RdRp action and this prevents the polymerase from making the viral RNA.
* It stops the virus from replicating its genes.
3. CQ/HCQ BINDS to SIALIC ACID:
* According to a research article
* Structure & molecular modeling studies reveal a new M.O.A. of CQ/HCQ against SARS-CoV-2 virus.
* It is well known that SARS-CoV-2 virus begins the replication process by attaching to the spike (S) viral protein of respiratory cell of the host cell.
* The S protein utilizes sialic acids and ACE-2 receptors connected to host cell surface gangliosides for entry.
* The study showed that CQ or its more active derivative, HCQ has a high affinity for binding to sialic acids.
* Sialic acid is essentially just a little piece of sugar & spike protein/ S-protein on the virus-cell can also actually bind to the sialic acid.
* So these sialic acid residues act like receptors for S-protein on the coronavirus as well.
CQ/HCQ binds to these sialic acid residues preventing the S-protein on the SARS CoV-2 virus from further binding to the sialic acid & essentially preventing the binding of the virus to the ACE-2 receptor as well.
* So the way CQ binds to the sialic acid prevents the proper binding of the SARS-CoV-2 virus to the ACE-2 receptor.
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