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Coronavirus protease structure guides optimization of inhibitor

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By solving the crystal structure of a SARS-CoV-2 protease, a University of Luebeck team was able to optimize a previously developed inhibitor for greater potency against the virus.

In a paper published in Science on Friday, the Luebeck group described the X-ray crystal structure of 3CLpro, which is key for the virus' replication, as well as the antiviral activity of an inhibitor tailored to the protease's structure.

Researchers at Diamond Light Source, the U.K.’s national synchrotron, uncovered the cryo-electron microscopy (cryo-EM) structure of the protease earlier this month.

In a pivot from a Journal of Medicinal study the Luebeck team had published in February, which sought a protease inhibitor that could be used against a wide range of coronaviruses, the group "sacrificed the goal of broad-spectrum activity" to boost potency against the clade to which SARS-CoV-2 belongs.

The authors had modified the α-ketoamide scaffold described in its previous study to have a longer plasma half-life and reduced binding to plasma proteins. Through computational analyses of the new structural data, they optimized that updated compound to enhance its binding to the SARS-CoV-2 protease.

The resulting compound inhibited the purified enzyme with an IC50 of 0.67 ± 0.18 μM, and inhibited SARS-CoV-2 viral replication in the human CALU-3 lung cancer cell line with an EC50 of 4-5 μM.

The compound showed no adverse effects and had favorable PK properties in mice, including tropism for lungs, a key disease site in COVID-19.

At least three other 3CLpro inhibiting therapies are being tested in the clinic to treat COVID-19. None contain an α-ketoamide scaffold (see "Where Clinical Products Intervene").

Available preclinical data for one of these therapies, the Kaletra lopinavir/ritonavir combination from AbbVie Inc. (NYSE:ABBV), shows it inhibits the replication of MERS-CoV in CALU-3 cells with an EC50 of 8.5 μM (see "Preclinical Potencies of Clinical COVID-19 Candidates").

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3CLpro (Coronavirus NSP5; Mpro) - Coronavirus 3C-like proteinase

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