If you want to disrupt COVID-19’s intricate self-replication machinery—and bring the virus to a screeching halt—you can’t simply throw a spanner in the works. Instead, you need to create some intricate machinery of your own, machinery that will mesh just so with COVID-19’s most vulnerable parts. Perhaps no part of COVID-19 is more vulnerable than its main protease. COVID-19 needs its main protease, which is called Mpro or 3CLpro, to form a viral replication complex.

This protease could be inhibited by an antiviral drug, provided the protease and the drug had complementary 3D shapes. Fortunately, the task of designing a drug that fits just got a little easier, thanks to a structural study completed by scientists based at the University of Lübeck. Using high-intensity x-ray light from the BESSY II facility of the Helmholtz-Zentrum Berlin, these scientists have elucidated the main protease’s 3D structure.

Details of the structure appeared March 20 in the journal Science, in an article titled, “Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.” In this article, x-ray structures are reported for the unliganded SARS-CoV-2 Mpro and for SARS-CoV-2 Mpro in a complex with an α-ketoamide inhibitor.

“This [inhibitor] was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma,” the article’s authors noted. “Based on the structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro.” To establish that the inhibitor’s pyridone ring was compatible with the three-dimensional structure of the target, the scientists determined the crystal structures at 1.75 Å resolution.

The scientists, led by Dr. Rolf Hilgenfeld, professor, further tested their leading inhibitor compound in mice. The inhibitor, called 13b, was administered via the inhalation route, and it was well tolerated. The mice did not show any adverse effects.

These findings, the scientists asserted, indicate that direct administration of the compound to the lungs may be possible. The scientists emphasized that their work could provide a framework for the development of drugs to combat the novel coronavirus.

“Now, our inhibitor will have to be developed into a drug,” declared Hilgenfeld. “For that, we have to get a pharmaceutical company on board, because only such a company would have the resources to finance clinical trials.” He added that he hopes to receive support from a consortium of companies and public research institutions (a private-public partnership) that is currently being formed as part of an initiative of the European Commission to fight the novel coronavirus.

“But for sure, it will take several years until our inhibitor will be turned into an anti-coronaviral drug,” he cautioned. “If everything were to go well, such a drug could be available for SARS-CoV-3, but certainly not during the current outbreak.

“In any case, we must uncouple antiviral research from the recurrent outbreaks of emerging viruses such as SARS-CoV-2 and make sure that we achieve more sustainable drug development.”

That is, besides being of immediate practical value to Hilgenfeld’s group, which is optimizing small-molecule alpha-ketoamide inhibitors, the current work forms the basis for the further development of additional compounds that could inhibit the main protease.

The main protease is a key enzyme in the life cycle of the coronavirus, as it processes the huge polyproteins, into which the viral RNA is initially translated after it has entered the interior of the human cell. The protease cuts 12 smaller proteins out of the polyproteins, which in turn are components of the replication complex involved in copying the viral RNA genome.

“If we succeed in inhibiting the main protease,” Hilgenfeld explained, “we can thus stop virus replication.”

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