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SARS-CoV-2 main protease (Mpro)
IntroductionThe Mpro protease (also known as 3CLpro), is a viral non-structural protein from the virus SARS-CoV-2 [1], responsible for a major outbreak of the disease called Coronavirus Disease 2019 (COVID-19), declared pandemic by WHO in 11 march 2020 [2]. 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]. 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 [1]. 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 [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) [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. StructureThe Mpro is a protein of approximately 30 kDa [5][6] consisting of two containing 306 amino acid residues each [1]. This monomers dimerize forming a [1]. Each chain consists of : I (; residues 10-99), II (; residues 100-182), and III (; residues 198-303). Domains I and II comprise six-stranded antiparallel and domain III comprises [1][6]. The substrate-binding site is located between domains I and II with the containing the amino acid residues [1]. 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 [1][7]. This dimerization regulation is mainly through a between Glu290 of one monomer and Arg4 of the other monomer.[1]. Moreover, the dimer has a that is predominantly between domain II of one monomer and the N-terminal residues of other monomer. Indeed, the N-terminal residue of each monomer interacts with Glu166 of the other monomer, helping shape the (notice how Glu166 is a key residue to shape the binding site).[1] Therefore, The N-terminal of one monomer interacts with the other monomer by the to help dimerization. Structural comparison with SARS-CoV MproAs mentioned above, SARS-CoV-2 Mpro has 96% sequence identity with SARS-CoV Mpro and as expected, also a highly similar three-dimensional structure [1]. Indeed, it has been shown that the substrate-binding pocket is a highly conserved region of Mpro among an important number of CoV Mpro [6]. 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 monomer, involving the residues Thr285, what is not found in the COVID-19 virus Mpro [1]. In fact, in SARS-CoV-2, the threonine is replaced by , an amino acid with hydrophobic side chain, leading to a higher proximity between the two domains III of the dimer [1]. An attractive drug targetAs have been shown, because of its importance for viral replication, inhibiting SARS-CoV-2 Mpro activity could lead to viral replication blockage [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 [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 provided useful framework for development of this kind of inhibitors toward coronaviruses [1]. It was showed that the interacts with the catalytic residue His41 and with residues Gly143 and Ser144 through hydrogen bonds, and that there is a nucleophilic attack of the catalytic Cys145 onto the α-keto group of the inhibitor. This can be seen in the formed between SARS-CoV-2 Mpro and the α-ketoamide inhibitor [1]. External Resources
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