COVID-19 News: Indian Study Finds That Picolinic Acid Is A Broad-Spectrum Inhibitor Of Enveloped Virus Including SARS-CoV-2 And Influenza A Virus!

COVID-19 News: The COVID-19 pandemic has brought the world to its knees, underscoring the urgent need for effective antiviral treatments. In the quest to combat viral infections, a team of researchers at the Indian Institute of Science in Bengaluru, India, has made a groundbreaking discovery. Their study reveals that Picolinic Acid (PA), a natural metabolite produced during the catabolism of tryptophan, is a broad-spectrum inhibitor of enveloped viruses, including the notorious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV). In this comprehensive COVID-19 News, we delve into the significance of this discovery, the mechanism of action behind PA's antiviral activity, and the promising results observed in pre-clinical animal models. This breakthrough offers hope in the fight against not only the ongoing COVID-19 pandemic but also other emerging and re-emerging enveloped viruses.


                                                                     Graphical Abstract
 
The Urgent Need for Broad-Spectrum Antivirals
Emerging and re-emerging viral pathogens are a constant threat to global public health. To effectively combat these viruses, there is an imperative need for broad-spectrum antiviral treatments. Conventional direct-acting antivirals, which target specific viral components, are susceptible to viral resistance, particularly in the case of RNA viruses. An example of this vulnerability can be seen in the development of resistance against nirmatrelvir, an inhibitor of the SARS-CoV-2 main protease, and oseltamivir, used against influenza A virus.

In contrast, host-directed antivirals, which target cellular factors essential for the viral life cycle, present a higher resistance barrier. By focusing on the cellular processes hijacked by viruses, researchers can develop treatments that are less prone to resistance.
 
Cellular Entry as a Vulnerable Target
One of the crucial host-dependent steps in the viral life cycle is cellular entry. Many human viral pathogens, especially those with pandemic potential, are enveloped viruses, including coronaviruses, influenza viruses, retroviruses, flaviviruses, and herpes viruses. These viruses all share the characteristic of viral-cellular membrane fusion during entry, making it an attractive target for the development of broad-spectrum antivirals.
 
The Role of Picolinic Acid (PA)
Picolinic acid, also known as pyridine-2-carboxylic acid, is a naturally occurring metabolite produced in mammals during the breakdown of tryptophan through the kynurenine pathway. Recently, Picolinic Acid (PA) was found to influence endosome maturation, a crucial step in viral entry, making it an ideal candidate for the development of broad-spectrum a ntiviral treatments.
 
The Broad-Spectrum Antiviral Activity of PA
The research explored the antiviral potential of PA against a wide range of human viral pathogens, including SARS-CoV-2, IAV, dengue virus (DENV), Zika virus (ZIKV), Japanese encephalitis virus (JEV), herpes simplex virus (HSV), human parainfluenza virus (HPIV), rotavirus, and coxsackie virus (CSV).
 
Mechanistic studies demonstrated that Picolinic Acid (PA) selectively inhibits the entry of enveloped viruses by targeting viral membrane integrity, preventing viral-cellular membrane fusion, and interfering with endocytic vesicle trafficking.
 
In pre-clinical animal models, Picolinic Acid (PA) showed promising antiviral efficacy against SARS-CoV-2 in the Syrian hamster model and IAV in the BALB/c murine model. These results open the door for further clinical development and use of PA as a versatile antiviral treatment to combat pandemic viruses, including SARS-CoV-2 and IAV.
 
Mechanism of Action
PA's mechanism of action against enveloped viruses lies in its ability to disrupt viral-cellular membrane fusion. As mentioned earlier, viral entry is a critical stage in the viral life cycle, and Picolinic Acid (PA) targets this process.
 
All the viruses tested in the study, including SARS-CoV-2, IAV, HSV-1, and flaviviruses, rely on a host-derived viral membrane during infection. IAV and flaviviruses require receptor-mediated endocytosis, while HSV-1 and SARS-CoV-2 predominantly enter cells through direct viral-cellular membrane fusion. PA's action appears to be directed towards the viral membrane, specifically inhibiting fusion between the viral and cellular endocytic membranes.
 
Notably, Picolinic Acid (PA) exhibited more potent antiviral activity against SARS-CoV-2 compared to IAV, indicating its effectiveness in inhibiting viral-cell membrane fusion during SARS-CoV-2 entry. This promising result is particularly significant in light of the ongoing COVID-19 pandemic.
 
Impact on Endosomal Positioning
Picolinic Acid (PA) treatment also had a notable impact on endosomal positioning within treated cells. Endosomes, which play a crucial role in viral entry, were observed to be dispersed away from the perinuclear region. This aligns with previous studies and further underscores PA's antiviral mode of action, particularly against viruses that rely on cellular endocytosis for entry.
 
Non-Enveloped Viruses Remain Unaffected
Intriguingly, the study found that Picolinic Acid (PA) had no effect on the entry of non-enveloped viruses like CSV, rotavirus, and Ad5, which also rely on receptor-mediated endocytosis for entry. The limited antiviral effect of PA on AAV6 infection may be due to its influence on cellular endocytosis.
 
PA's ability to specifically target enveloped viruses without affecting non-enveloped viruses or bacteriophages suggests that its antiviral action has evolved in higher organisms primarily against enveloped viruses, which enter cells via viral-cellular membrane fusion.
 
Disruption of Viral Membrane Integrity
Examination of Picolinic Acid (PA)-treated IAV virions through transmission electron microscopy revealed a disruption in viral membrane integrity. This disruption is believed to be responsible for impairing viral-cellular membrane fusion. Importantly, PA's effect on cellular membrane integrity was not apparent, indicating that the cellular membrane can recover, while the viral membrane cannot. Antivirals based on similar principles have been reported in the past, making PA a promising candidate for further development.
 
Promising Results in Pre-Clinical Animal Models
One of the most exciting aspects of this research is the promising results observed in pre-clinical animal models. Picolinic Acid (PA) was found to restrict IAV replication and pathogenesis in the murine model, particularly when administered prophylactically, aligning with its mechanism of action targeting early events in viral infection. Furthermore, PA exhibited no toxicity in animals up to a dose of 100 mg/kg, which is equivalent to 8 mg/kg in humans.
Additional immunomodulatory properties of Picolinic Acid (PA) were observed in animal studies, with an increase in the CD4-positive T cell population in the lungs of PA-treated mice. This suggests that PA's effects extend beyond viral entry inhibition, potentially enhancing the immune response.
 
Conclusion
The discovery of Picolinic Acid (PA) as a broad-spectrum inhibitor of enveloped viral entry offers a ray of hope in the battle against emerging and re-emerging enveloped viruses, including SARS-CoV-2 and IAV. Picolinic Acid (PA)'s ability to selectively target viral-cellular membrane fusion, without affecting non-enveloped viruses, underscores its potential as a versatile antiviral treatment. Promising results in pre-clinical animal models, coupled with its low toxicity, make PA an attractive candidate for further clinical development.
 
As the world continues to grapple with the COVID-19 pandemic and the looming threat of future viral outbreaks, the research serves as a beacon of hope. Picolinic Acid may well prove to be a powerful tool in our arsenal to combat these formidable adversaries and ensure global public health and safety in the face of emerging and re-emerging viral pathogens.
 
The study findings were published in the peer reviewed journal: Cell Reports Medicine.
https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(23)00255-0
 
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