Dihydroorotate Dehydrogenase Inhibitor as Potential COVID-19 Therapeutic

Researchers in the US report a new orally used compound known as “PTC299” which is a potent inhibitor of dihydroorotate dehydrogenase (DHODH). SARS-COV-2 is a single-stranded RNA virus that enters the human host cell via its attachment to the ACE2 receptor, a membrane protein in the renin-angiotensin pathway. The virus binds itself to the S1 subunit of the enzyme and undergoes endocytosis to internalize into the host cell. This is followed by the escape of the post-fusion virus from the endosome and enters the cytoplasm. It then replicates rapidly which triggers a cytokine storm. This leads to increased accessibility of blood vessels, multi-organ dysfunction, ARDS, and death.

The researchers attempted to find a compound that can both prevent the replication of the virus while also reducing the cytokine levels. DHODH is an enzyme encoded by the gene on chromosome 16. It is the rate-limiting enzyme in the pyrimidine biosynthesis pathway. It controls the level of pyrimidines. The molecule PTC299 is a top contender among the molecules identified by a recent multi-omics study to have a high potential for coronavirus treatment. This molecule is a potent inhibitor of this enzyme. It displays two different mechanisms of benefit in the treatment of COVID-19, making it different from most other therapeutic molecules under investigation currently.

This property also means it is useful for both early and late disease in COVID-19. In contrast, direct-acting antivirals are most effective when started early. Secondly, the unique mechanism of action means that viruses are very rarely going to develop resistance since they cannot forego the need for pyrimidines in RNA synthesis. 

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Ref link: https://www.biorxiv.org/content/10.1101/2020.08.05.238394v1