User:Dora Bonadio/Sandbox 1
From Proteopedia
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The Mpro protease (also known as 3CLpro), is a viral non structural protein from the virus SARS-CoV-2 <ref name="Crystal_structure">PMID:32198291</ref>, responsible for a major outbreak of the disease called COVID-19, declared pandemic by WHO in 11 march 2020 <ref name="WHO">WHO. COVID-19 situation reports [Internet]. [cited 2020 May 15]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports | The Mpro protease (also known as 3CLpro), is a viral non structural protein from the virus SARS-CoV-2 <ref name="Crystal_structure">PMID:32198291</ref>, responsible for a major outbreak of the disease called COVID-19, declared pandemic by WHO in 11 march 2020 <ref name="WHO">WHO. COVID-19 situation reports [Internet]. [cited 2020 May 15]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports | ||
| - | </ref>. It has an important role in virus replication, as it’s responsible for cleavage of the polyproteins of the virus, alongside with papain-like protease(s) (3). | + | </ref>. It has an important role in virus replication, as it’s responsible for cleavage of the polyproteins of the virus, alongside with papain-like protease(s) <ref name="sars_mers">PMID:25039866</ref>(3). |
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue. | You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue. | ||
== Function == | == Function == | ||
| - | The Mpro protein function is mainly deduced from the function of SARS-CoV virus Mpro , which has a 96% amino acid identity and a highly similar three-dimensional structure with SARS-CoV-2 Mpro <ref name="Crystal_structure" />. As a protease, Mpro is an enzyme that causes proteolysis, which means that it breaks protein peptide bonds by hydrolysis (4). Indeed, the Mpro processes the replicase polyprotein 1ab (pp1ab ~790 kDa) translated from the viral RNA ORF1ab <ref name="Crystal_structure" />(1, 5). In fact, Mpro cleaves 11 sites of pp1ab and the recognition sequence at most sites is between Leu-Gln and (Ser, Ala, Gly) <ref name="Crystal_structure" />(1, 3). Proteins resulting from this polyprotein cleavage are non-structural proteins (NSPs) and they seem to contribute with viral replication and transcription (5). Thus, by processing an important number of non-structural proteins, this enzyme plays a critical role in SARS-CoV-2 replication. | + | The Mpro protein function is mainly deduced from the function of SARS-CoV virus Mpro , which has a 96% amino acid identity and a highly similar three-dimensional structure with SARS-CoV-2 Mpro <ref name="Crystal_structure" />. As a protease, Mpro is an enzyme that causes proteolysis, which means that it breaks protein peptide bonds by hydrolysis (4). Indeed, the Mpro processes the replicase polyprotein 1ab (pp1ab ~790 kDa) translated from the viral RNA ORF1ab <ref name="Crystal_structure" />(1, 5). In fact, Mpro cleaves 11 sites of pp1ab and the recognition sequence at most sites is between Leu-Gln and (Ser, Ala, Gly) <ref name="Crystal_structure" /><ref name="sars_mers" />(1, 3). Proteins resulting from this polyprotein cleavage are non-structural proteins (NSPs) and they seem to contribute with viral replication and transcription (5). Thus, by processing an important number of non-structural proteins, this enzyme plays a critical role in SARS-CoV-2 replication. |
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== Structural comparison with SARS-CoV M<sup>pro</sup> == | == Structural comparison with SARS-CoV M<sup>pro</sup> == | ||
| - | 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" />(1, 6). 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 (3). Therefore, CoV Mpro has been an attractive drug target among coronaviruses (3) and so it is for COVID-19 <ref name="Crystal_structure" />(1, 6). 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 (6, 8) . 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" />. | + | 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" />(1, 6). 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" />(3). Therefore, CoV Mpro has been an attractive drug target among coronaviruses <ref name="sars_mers" />(3) and so it is for COVID-19 <ref name="Crystal_structure" />(1, 6). 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 (6, 8) . 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" />. |
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes. | This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes. | ||
Revision as of 02:58, 9 June 2020
SARS-CoV-2 main protease (Mpro)
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