Designing of improved drugs for COVID-19: Crystal structure of SARS-CoV-2 main protease M pro

摘要

Recently, Zhang and colleagues published a study in Sciencewhich reports about the crystal structure of the main protease(Mpro, 3CLpro) of SARS-CoV-21. The authors reported the X-raystructure of unliganded SARS-CoV-2 Mpro and its complex withα-ketoamide inhibitor after a modification from the previouslydesigned inhibitor through incorporating P3-P2 amidebond into pyridone ring so as to increase its half-life inplasma. Finally the authors demonstrated that the crystalstructure of Mpro provides a basis for designing of a potentinhibitor to the protease with a marked tropism to the lungand with ease of administration through inhalation.An outbreak of series of acute respiratory illness caused by anovel coronavirus, SARS-CoV-2, caused a global threat in 20202.The world health organization (WHO) named the disease “COVID19”and declared it as a world health emergency pandemic.Studying the crystal structure of targets for treatment is verycrucial to know the mechanism of action of prospective drugs. Astructural study on the coronavirus main protease 3CLpro inhibitorcomplex established designing of broad-spectrum halomethylketone inhibitors to the Coronaviridae family and demonstratedthat these inhibitors form a thioether linkage with high affinity tothe target3. Hilgenfeld’s group reported earlier that a structurebaseddesign of peptidomimetic α-ketoamides are also effectivebroad-spectrum inhibitors to the main and 3C protease ofcoronaviruses and enteroviruses as demonstrated by crystalstructure of inhibitor-protease complex4. The 3CL protease ofcoronaviruses facilitates viral assembly by cleaving polyproteinsand most active compounds prevent disease progression byinhibiting viral proteases 5.