COVID-19 Drugs: New In Vitro Study Shows That The High Blood Pressure Drug Losartan Inhibits SARS-CoV-2 Replication

COVID-19 Drugs: A new in vitro study conducted by researchers from University of Georgia-US and Shahid Beheshti University-Iran has found that the common high pressure drug called Losartan is able to inhibit SARS-CoV-2 coronavirus replication.
 
Losartan, sold under the trade name Cozaar among others, is a medication mainly used to treat high blood pressure. Losartan belongs to a group of drugs called angiotensin II receptor antagonists. It keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow. It is also used for diabetic kidney disease, heart failure, and left ventricular enlargement. It is taken by mouth. It may be used alone or in addition to other blood pressure medication
 
The study team tested the effect of angiotensin II type I receptor blocker, losartan, on SARS-CoV-2 replication and inhibition of the papain-like protease of the virus. 
 
The dose-dependent inhibitory effect of losartan, in concentrations from 1μM to 100μM as determined by quantitative cell analysis combining fluorescence microscopy, image processing, and cellular measurements (Cellomics analysis) on SARS-CoV-2 replication was investigated in Vero E6 cells. The impact of losartan on deubiquitination and deISGylation of SARS-CoV-2 papain-like protease (PLpro) were also evaluated.  
 
The study findings showed that losartan reduced PLpro cleavage of tetraUbiquitin to diUbiquitin.  It was less effective in inhibiting PLpro’s cleavage of ISG15-AMC than Ubiquitin-AMC.  To determine if losartan inhibited SARS-CoV-2 replication, losartan treatment of SARS-CoV-2 infected Vero E6 was examined. Losartan treatment one hour prior to SARS-CoV-2 infection reduced levels of SARS-CoV-2 nuclear protein, an indicator of virus replication, by 80% and treatment one-hour post-infection decreased viral replication by 70%. 
 
The study findings found that losartan was not an effective inhibitor of deubiquitinase or deISGylase activity of the PLpro but affected the SARS-CoV-2 replication of Vero E6 cells in vitro.  As losartan has a favorable safety profile and is currently available it has features necessary for efficacious drug repurposing and treatment of COVID-19.
 
The study findings were published in the peer reviewed Journal of Pharmacy and Pharmaceutical Sciences. https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/31931
 
The COVID-19 disease, which is caused by the SARS-CoV-2 coronavirus, has already claimed more than 4.3 million lives worldwide and infected more than 200 million people over the last 19 months. It is expected in the next few months, surges with the delta, lambda and other newly emerging variants might triple these figures in a short span.
 
The SARS-CoV-2 coronavirus is a single-stranded positive-sense RNA virus belonging to the Coronaviridae family. Other members of this family include the Middle East Respiratory Syndrome (MERS) and the severe acute respiratory coronavirus (SARS-CoV-1).
 
To date, there are no effective antiviral drugs for the treatment of COVID-19 and vaccine rollout has been quite heterogeneous across different countries. Furthermore, studies are emerging that the new variants are making the current vaccines less effective.
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As such scientists have turned to drug repurposing as a potentially promising strategy to combat the disease.
 
Importantly a globally available and safe drug that has properties that could ameliorate the pathological changes of COVID-19 with minimum side effects, in particular, could greatly impact the management of the current pandemic. A better understanding of the features of COVID-19 pathogenesis can also assist in drug repurposing and discovery.
 
This new study explores the use of Losartan to provide protection against COVID-19 pathogenesis.
 
It has been known that the downregulation of angiotensin-converting enzyme 2 (ACE2) has been shown to cause local RAS dysregulation. This can subsequently lead to pro-inflammatory, pro-apoptotic, and pro-thrombotic effects and, ultimately, COVID-19-induced cytokine storm.
 
The study team hypothesized that selective AT1R antagonism by angiotensin receptor blockers (ARBs) can aid in reducing COVID-19-related lung pathology.

Angiotensin receptor blockers or ARBs achieve this by rebalancing the Ang II/angiotensin (1-7) ratio and by indirectly promoting Ang II-induced activation of AT2R.
 
Previous studies have found that C21, which is an antagonist of AT2R, improved respiratory function in the hospitalization and mortality rates of COVID-19 patients. https://www.medrxiv.org/content/10.1101/2021.01.26.21250511v1
 
Notably, during the initial phases of the pandemic, the use of ARBs was limited owing to concerns over their possibility to increase its viral load, due to ACE2 upregulating effects. Further research has since proven that this is not the case and experimental and clinical studies on ARBs in COVID-19 are well underway.
 
Interestingly in recent in silico studies, losartan, which is an ARB, was shown to change the structure of ACE2, thereby affecting its binding with the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. https://pubmed.ncbi.nlm.nih.gov/33294307/
 
Losartan was also found to reduce inflammatory responses that would otherwise lead to acute respiratory distress and change the atomic configuration of SARS-CoV-2 PLpro. https://pubmed.ncbi.nlm.nih.gov/28483563/
 
The study team scientists examined the ability of losartan to inhibit the deubiquitinase and deISGylase properties of SARS-CoV-2 PLpro. The team also examined whether losartan was capable of preventing viral replication in pre-and post-infected Vero E6 cells.
 
For the study, losartan was first incubated at various concentrations with SARS-CoV-2 PLpro and a peptide substrate, which contained interferon-stimulated gene product 15 (ISG15). The results of this experiment suggested that losartan could be interacting with certain elements of PLpro that are capable of accommodating peptide and Ub-like substrates. The inhibition rate of losartan was 2.3% when tested against Ub-AMC and 6.9% against ISG15 cleavage.
 
However with regards to the effects of losartan on Tetra-Ub Deubiqutination at 2mM, losartan showed a small reduction in deISGylase activity as compared to the control.
 
Importantly further, treatment of Vero E5 cells with losartan showed a dose-dependent (0-100 µM) effect on SARS-CoV-2 replication.
 
The study findings demonstrate the weak inhibitory effect of losartan on viral PLpro deubiquitinase and deISGylase properties. Albeit dose-dependent, the treatment of Vero E6 cells with losartan inhibited viral replication.
 
The tea says that despite obtaining some initially promising results, more extensive research is required to gain a better understanding of the structural changes that occur in the viral proteins and their biological products when interacted with losartan.
 
Should these further studies yield viable results, it could open up new avenues for effective antiviral design and development. More research is using diversified cohorts in randomized control trials would also be necessary in order to better understand the effect of Losartan in the future stages of the pandemic.
 
It should be noted that two of the main advantages associated with losartan are that it is not toxic to cells and has inhibitory effects on viral replication. These features may immensely help in curbing the spread of COVID-19 and managing individuals who are unresponsive to vaccination.
 
Furthermore there is also a possibility that losartan is effective against future mutants of SARS-CoV-2. All of these crucial issues warrant more research. Promising results would imply easing the burden of healthcare costs globally.
 
Thailand Medical News however warns that this is only a in vitro study and that no one should ever contemplate self-treating with losartan without consulting a licensed qualified doctor first.
 
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