User:Dora Bonadio/Sandbox 1: Difference between revisions

The Mpro is a protein of approximately 30 kDa <ref name="replication" /><ref name="ofmpro">Jin, Zhenming, Xiaoyu Du, Yechun Xu, Yongqiang Deng, Meiqin Liu, Yao Zhao, Bing Zhang, et al. 2020. ‘Structure of M pro from SARS-CoV-2 and Discovery of Its Inhibitors’. Nature, April, 1–5. https://doi.org/10.1038/s41586-020-2223-y. </ref> consisting of <scene name='84/845941/Assembly/3'>two protomers</scene> containing 306 amino acid residues each <ref name="Crystal_structure" />. This protomers dimerize forming a homodimer <ref name="Crystal_structure" />. Each protomer consists of <scene name='84/845941/Domains/1'>three domains</scene>: I (<scene name='84/845941/Domaini/1'>chymotrypsin-like</scene>; residues 10-99), II (<scene name='84/845941/Domains2/1'>picornavirus 3C protease-like</scene>; residues 100-182), and III (<scene name='84/845941/Domains3/1'>a globular cluster</scene>; residues 198-303). Domains I and II comprise six-stranded antiparallel β-barrels and domain III comprises five α-helices <ref name="Crystal_structure" /><ref name="ofmpro" />. The substrate-binding site is located between domains I and II with the catalytic site containing the amino acid residues Cys145 and His41 <ref name="Crystal_structure" />. Domain III, in turn, has been shown to be involved in the regulation of Mpro dimerization, what is necessary for the catalytic activity of this enzyme once it helps to shape the substrate-binding site <ref name="Crystal_structure" /><ref name="reveals"> PMID:12093723</ref>.  

As mentioned above, SARS-CoV-2 Mpro has 96% sequence identity with SARS-CoV Mpro and as expected, also a highly similar three-dimensional structure <ref name="Crystal_structure" />. Indeed, it has been shown that the substrate-binding pocket is a highly conserved region of Mpro among an important number of CoV Mpros <ref name="ofmpro" />. However, an interesting difference found between SARS-CoV Mpro and SARS-CoV-2 Mpro is that in the first one there is a polar interaction between the domains III of each protomer, involving the residues Thr285, what is not found in the COVID-19 virus Mpro <ref name="Crystal_structure" />. In fact, in SARS-CoV-2, the threonine is replaced by alanine, leading to a higher proximity between the two domains III of the dimer <ref name="Crystal_structure" />.  

As have been shown, because of its importance for viral replication, inhibiting SARS-CoV-2 Mpro activity could lead to viral replication blockage <ref name="Crystal_structure" /><ref name="ofmpro" />. Moreover, no human proteases has been reported to have a similar cleavage specificity and so, in this aspect, Mpro inhibitors toxic side-effects may be reduced <ref name="sars_mers" />. Therefore, CoV Mpro has been an attractive drug target among coronaviruses <ref name="sars_mers" /> and so it is for COVID-19 <ref name="Crystal_structure" /><ref name="ofmpro" />. Indeed, virtual drug screening, structure-assisted drug design, and high-throughput screening are been used to repurpose approved pharmaceutical drug and drug candidates targeting SARS-CoV-2 Mpro <ref name="ofmpro" /><ref name="elucidation"> Mirza, Muhammad Usman, and Matheus Froeyen. 2020. ‘Structural Elucidation of SARS-CoV-2 Vital Proteins: Computational Methods Reveal Potential Drug Candidates against Main Protease, Nsp12 Polymerase and Nsp13 Helicase’. Journal of Pharmaceutical Analysis, April. Doi:[https://doi.org/10.1016/j.jpha.2020.04.008].</ref>. Furthermore, a study carrying the pharmacokinetic characterization of an optimized Mpro α-ketoamide inhibitor provides useful framework for development of this kind of inhibitors toward coronaviruses <ref name="Crystal_structure" />. It was showed that the α-ketoamide inhibitor interacts with the catalytic site of the enzyme through two hydrogen bonding interactions, as can be seen in the complex formed between SARS-CoV-2 Mpro and an α-ketoamide inhibitor <ref name="Crystal_structure" />.