Self-Replication Machinery of COVID-19 Has Been Revealed to Drug Designers

You can't just put a spanner in COVID-19's complex self-replication machinery and bring the virus to a halt. Instead, you'll need to create your own complex machinery that will perfectly match COVID-19's most fragile pieces. COVID-19's main protease is perhaps the most susceptible component of the virus. To form a viral replication complex, COVID-19 requires its key protease, Mpro or 3CLpro.

An antiviral drug could inhibit this protease if the protease and the drug had complementary 3D shapes. Fortunately, thanks to a structural analysis conducted by scientists at the University of Lübeck, the challenge of developing a medication that works has just become a little easier. These researchers used high-intensity x-ray light from the Helmholtz-Zentrum Berlin's BESSY II facility to deduce the 3D structure of the main protease.

Details of the structure publish on March 20 in the journal Science, in an article under titled, “Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.”The unliganded SARS-CoV-2 Mpro and SARS-CoV-2 Mpro in a complex with a -ketoamide inhibitor have x-ray structures mentioned in this paper.

“This [inhibitor] was derived from a previously designed inhibitor, but with the P3-P2 amide bond inserted into a pyridone ring to increase the compound's half-life in plasma,” the authors wrote. “We transformed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro based on the structure.” The crystal structures of the inhibitor's pyridone ring were calculated at 1.75 resolution to ensure that it was consistent with the target's three-dimensional structure.

The researchers, led by professor Rolf Hilgenfeld, tested their leading inhibitor compound in mice. The inhibitor, known as 13b, was given to patients via inhalation and was well tolerated. There were no negative effects on the mice.

According to the researchers, these results suggest that the compound should be administered directly to the lungs. The researchers stated that their findings may serve as a foundation for the creation of drugs to combat the novel coronavirus.

“Now we have to transform our inhibitor into a drug,” Hilgenfeld said. “And do so, we need to bring in a pharmaceutical firm, and only a pharmaceutical company has the resources to fund clinical trials.” He also expressed hope for funding from a group of corporations and public research institutions (a private-public partnership) that is currently being developed as part of a European Commission initiative to combat the novel coronavirus.

“However, it will undoubtedly take many years before our inhibitor is developed into an anti-coronaviral drug,” he warned. “If all goes well, a treatment for SARS-CoV-3 may be available in the future, but not during the current outbreak.

“In any case, we need to decouple antiviral research from the recurrent outbreaks of emerging viruses like SARS-CoV-2 and ensure more long-term drug development.”

That is, in addition to being immediately useful to Hilgenfeld's group, which is working to improve small-molecule alpha-ketoamide inhibitors, the current research lays the groundwork for the discovery of additional compounds that could inhibit the main protease.

The main protease is an important enzyme in the coronavirus life cycle since it processes the large polyproteins into which the viral RNA is first converted after entering the human cell. The protease breaks down the polyproteins into 12 smaller proteins, which are then used by the replication complex to replicate the viral RNA genome.

“If we can inhibit the key protease, we will be able to stop virus replication,” Hilgenfeld said.