Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease.

The main protease M is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among the first reported M inhibitors was the peptidomimetic α-ketoamide , whose cocrystal structure with M paved the way for multiple lead-finding studies. We established structure-activity relationships for the series by modifying residues at the P1', P3, and P4 sites.

Practical courses on advanced methods in macromolecular crystallization: 20 years of history and future perspectives.

The first Federation of European Biochemical Societies Advanced Course on macromolecular crystallization was launched in the Czech Republic in October 2004. Over the past two decades, the course has developed into a distinguished event, attracting students, early career postdoctoral researchers and lecturers. The course topics include protein purification, characterization and crystallization, covering the latest advances in the field of structural biology.

Profiling of coronaviral M and enteroviral 3C specificity provides a framework for the development of broad-spectrum antiviral compounds.

The main protease from coronaviruses and the 3C protease from enteroviruses play a crucial role in processing viral polyproteins, making them attractive targets for the development of antiviral agents. In this study, we employed a combinatorial chemistry approach-HyCoSuL-to compare the substrate specificity profiles of the main and 3C proteases from alphacoronaviruses, betacoronaviruses, and enteroviruses. The obtained data demonstrate that coronavirus Ms exhibit overlapping substrate specificity in all binding pockets, whereas the 3C from enterovirus displays slightly different preferences toward natural and unnatural amino acids at the P4-P2 positions.

Why is the Omicron main protease of SARS-CoV-2 less stable than its wild-type counterpart? A crystallographic, biophysical, and theoretical study of the free enzyme and its complex with inhibitor 13b-K.

During the continuing evolution of SARS-CoV-2, the Omicron variant of concern emerged in the second half of 2021 and has been dominant since November that year. Along with its sublineages, it has maintained a prominent role ever since. The Nsp5 main protease (M) of the Omicron virus is characterized by a single dominant mutation, P132H.