PTC299 inhibits SARS-CoV-2 replication and suppresses inflammatory cytokine production

The 2019 coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a serious global public health crisis. To date, the virus has infected 63.75 million people and has caused the deaths of over 1.47 million worldwide, showing that there is an urgent need for effective therapeutic treatments to combat this disease.

SARS-CoV-2 is a single-stranded RNA virus from the Coronaviridae family that is 79.5% similar to SARS-CoV-1 in terms of genetic sequence.

In the early stages of COVID-19, the virus multiplies rapidly and causes mild to severe symptoms. In severe cases, it triggers a cytokine storm characterized by excessive production of inflammatory cytokines. This uncontrolled inflammation can lead to hyperpermeability of the vascular system, acute respiratory distress syndrome, multiple organ failure and death.

Acute respiratory distress syndrome is one of the most common causes of COVID-19-related mortality. Additionally, increased levels of interleukin (IL) -6 and IL-17 are said to be linked to severe lung complications and death.

A potent bioavailable inhibitor of dihydroorotate dehydrogenase

PTC299 is an orally bioavailable inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine biosynthesis pathway.

Studies have shown that cultured cells treated with PTC299 can inhibit DHODH activity, leading to increased levels of DHO (substrate enzyme DHODH). In other studies, cancer patients treated with PTC299 had increased levels of DHO in their blood, indicating successful inhibition of DHODH in these patients.

PTC299 was generally well tolerated and exhibited a favorable pharmacokinetic profile in cancer patients in large studies, supporting the study of PTC299 for use in the treatment of COVID-19.

Evaluation of the antiviral activity of PTC299 against SARS-CoV-2

In an article published in the journal Virus research, a team of researchers from various US institutions discussed their study that evaluated the antiviral activity of PTC299 against a group of RNA viruses in vitro.

The specific objective of the study was SARS-CoV-2 and they also evaluated the ability of PTC299 to reduce the uncontrolled production of inflammatory cytokines in patients with severe COVID-19.

The researchers described the anti-COVID-19 potential of PTC299 in tissue culture, where it exhibits dose-dependent and DHODH inhibition of SARS-CoV-2 replication with a selectivity index greater than 3,800. PTC299 also inhibited the replication of other RNA viruses such as the Ebola virus and also blocked the production of IL-6, IL-17A, IL-17 F and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of favorable human pharmacokinetic and safety profiles, cytokine inhibitory activity, and anti-SARS-CoV-2 activity makes PTC299 a promising treatment option for COVID-19.

“PTC299 is a very potent SARS-CoV-2 replication inhibitor that also suppresses the production of a subset of pro-inflammatory cytokines, suggesting it has the potential to act through this dual mechanism to treat the viral and immune components of COVID- 19. “

PTC299 inhibits SARS-CoV-2 replication and also suppresses cytokine production

Based on these results, the authors concluded that PTC299 is a potent SARS-CoV-2 replication inhibitor that also suppresses the production of pro-inflammatory cytokines, suggesting a dual mechanism of action that can help treat viral components. and immune systems of COVID-19. Due to its ability to inhibit both viral replication and cytokine production, the authors believe that PTC299 may be an effective option for treating both the early and later stages of COVID-19.

The dual action of PTC299 is in contrast to direct acting antivirals which are mostly effective in the early stage of the disease and to anti-inflammatory drugs which are effective only in the later stage of COVID-19.

“The new dual mechanism of action of PTC299 distinguishes it from most other therapies studied in the clinic for the treatment of COVID-19, as many of these target specific viral processes or the immune response, but not both.”

Studies have shown that combining antiviral therapy with immunosuppressants is crucial because the use of molecules that only control cytokine storms can make viral clearance difficult.

To summarize, PTC299 is orally bioavailable, has been extensively studied in humans, has well established pharmacokinetic and safety profiles and is well tolerated, all of which and previous clinical experience with the compound support the further development of this. molecule for use in COVID-19 treatment.

“These results and previous clinical experience with PTC299 support the further development of this new molecule for the treatment of COVID-19.”