The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a severe global public health crisis. As of today, the virus has infected 63.75 million people and claimed the lives of over 1.47 million worldwide, showing that there is an urgent need for effective therapeutic treatments to fight this disease.
SARS-CoV-2 is a single-stranded-RNA virus of the Coronaviridae family that is 79.5% similar to SARS-CoV-1 in terms of genetic sequence.
In the early phases 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 vasculature, acute respiratory distress syndrome, multi-organ failure, and death.
Acute respiratory distress syndrome is one of the most common causes of COVID-19-related mortality. In addition, increased levels of interleukin (IL)-6 and IL-17 are said to be linked to severe pulmonary complications and death.
A bioavailable potent 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 DHO (DHODH enzyme-substrate) levels. In other studies, cancer patients treated with PTC299 had increased blood DHO levels, indicating successful DHODH inhibition in these patients.
PTC299 has been generally well tolerated and manifested a favorable pharmacokinetic profile in oncology patients in extensive studies, supporting the investigation of PTC299 for use in the treatment of COVID-19.
Evaluating 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 focus of the study was SARS-CoV-2, and they also assessed the ability of PTC299 to reduce the uncontrolled production of inflammatory cytokines in severe COVID-19 patients.
The researchers described the anti-COVID-19 potential of PTC299 in tissue culture, where it manifests dose- and DHODH-dependent inhibition of SARS-CoV-2 replication with a selectivity index greater than 3,800. PTC299 also inhibited 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 pharmacokinetic and human safety profiles, cytokine inhibitory activity, and anti-SARS-CoV-2 activity renders PTC299 a promising treatment option for COVID-19.
“PTC299 is a highly potent inhibitor of SARS-CoV-2 replication that also suppresses 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 findings, the authors concluded that PTC299 is a potent inhibitor of SARS-CoV-2 replication that also suppresses the production of pro-inflammatory cytokines, suggesting a dual mechanism of action that can help treat the viral and immune components of COVID-19. Owing to its ability to inhibit both viral replication and cytokine production, the authors think that PTC299 may be an effective option for treating both early and later stages of COVID-19.
The dual action of PTC299 is in contrast with direct-acting antivirals that are mostly effective in the early phase of the disease and with anti-inflammatory drugs that are effective only in the later phase of COVID-19.
“The novel dual mechanism of action of PTC299 distinguishes it from most other therapeutics being investigated in the clinic for the treatment of COVID-19, as many of these target either viral-specific processes or the immune response, but not both.”
Studies have shown that it is vital to combine antiviral therapy with immune suppressants because using molecules that control only the cytokine storms may make viral clearance difficult.
To summarize, PTC299 is orally bioavailable, has been widely studied in humans, has well established pharmacokinetic and safety profiles and is tolerated well, all of which and prior clinical experience with the compound endorse further development of this molecule for use in COVID-19 treatment.
“These findings and prior clinical experience with PTC299 support the further development of this novel molecule for the treatment of COVID-19.”
- Jeremy Luban, Rachel Sattler, Elke Mühlberger, Jason D. Graci, Liangxian Cao, Marla Weetall, Christopher Trotta, Joseph M. Colacino, Sina Bavari, Caterina Strambio-De-Castillia, Ellen L. Suder, Yetao Wang, Veronica Soloveva, Katherine Cintron-Lue, Nikolai A. Naryshkin, Mark Pykett, Ellen M. Welch, Kylie O’Keefe, Ronald Kong, Elizabeth Goodwin, Allan Jacobson, Slobodan Paessler, Stuart Peltz, The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines, Virus Research, 2020, https://doi.org/10.1016/j.virusres.2020.198246, http://www.sciencedirect.com/science/article/pii/S0168170220311539