Defeating a virus takes learning to target its vulnerabilities. The COVID-19 vaccines, for example, taught our bodies to recognise the spike protein, which the virus uses to enter cells, and build a protective response against infection. As SARS-CoV-2 kept evolving, mutant forms of the spike protein allowed these new viral variants to evade immunity.
Luckily, the spike protein isn’t the virus’ only vulnerability. To treat COVID-19 infections, one enticing target is the coronavirus main protease (Mpro), an enzyme that cuts the viral polyprotein into smaller fragments which form functional viral proteins required by the virus to replicate and survive in the human body. Drugs that inhibit Mpro can prevent virus replication and effectively reduce viral loads of infected patients.
“Mpro is highly conserved amongst coronaviruses, which allows us to design inhibitors to combat multiple strains,” said Jia Yi Fong, a Senior Scientist at A*STAR’s Experimental Drug Development Centre (EDDC), who saw that the full potential of Mpro inhibitors had yet to be unlocked.
By targeting this highly conserved viral enzyme, Fong and the EDDC multidisciplinary research team, including Senior Principal Scientist Brian Chia and former Associate Director of Discovery Chemistry Joseph Cherian, aimed to develop a drug that could remain effective across different SARS-CoV-2 strains along with other coronaviruses.
The researchers began by designing substrate-like compounds that fit into the active site of Mpro, followed by chemical modifications to enhance their binding affinities. Several rounds of testing later, the team’s preclinical development candidate, currently called compound 18, could efficiently penetrate virus-infected cells to inhibit virus replication and reduce viral load significantly.
In cultured cells, compound 18 inhibited several SARS-CoV-2 variants, including alpha, beta, delta and omicron, as well as other coronaviruses such as MERS-CoV. Treating mice infected with SARS-CoV-2 led to reduced viral load in the lungs. The compound also performed well in pharmacokinetic studies across mice, rats, dogs and monkeys, suggesting it was metabolically stable.
“Our preclinical studies showed that compound 18 can reach target cells in infected animals and the lack of toxicity suggested a favourable safety profile,” said Fong, adding that clinical trials are the next step to confirm the drug candidate’s activity and safety.
The researchers have since filed a patent and hope that their broad-spectrum antiviral can not only combat COVID-19 but also strengthen preparedness for future coronavirus outbreaks.
The A*STAR-affiliated researchers contributing to this research are from the A*STAR Experimental Drug Development Centre (A*STAR EDDC).
