User:Megan Harris./Sandbox 1: Difference between revisions
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== Structure and Mechanism of Elbasvir == | == Structure and Mechanism of Elbasvir == | ||
Elbasvir, MK-8742,a tetra-cyclic indole based NS5A inhibitor, was experimentally obtained through the modification of MK-4882. MK-4882 was one of the first clinical candidate drugs as an NS5A inhibitor. Although initially effective, viral breakthrough was a concern which led to continue development of compounds that would be effective against multiple genotypes as well as NS5A mutations. Through efficacy studies of infected chimpanzees, Elbasvir was discovered as a diastereomer of the known compound, MK-4882 <ref>DOI: 10.1002/cmdc.201300343</ref>. Elbasvir has a structural formula of C<sub>49</sub>H<sub>55</sub>N<sub>9</sub>O<sub>7</sub> and a molecular weight of 882.035 g/mol. It is a highly flexible protein with 13 rotatable bonds. It has four hydrogen bond donors and nine hydrogen bond acceptors <ref>National Center for Biotechnology Inforamtion. PubChem Compound Database; CID=71661251, https://pubchem.ncbi.nlm.nih.gov/compound/71661251#section=Chemical-and-Physical-Properties</ref>. | Elbasvir, MK-8742,a tetra-cyclic indole based NS5A inhibitor, was experimentally obtained through the modification of MK-4882. MK-4882 was one of the first clinical candidate drugs as an NS5A inhibitor. Although initially effective, viral breakthrough was a concern which led to continue development of compounds that would be effective against multiple genotypes as well as NS5A mutations. Through efficacy studies of infected chimpanzees, Elbasvir was discovered as a diastereomer of the known compound, MK-4882 <ref>DOI: 10.1002/cmdc.201300343</ref>. Elbasvir has a structural formula of C<sub>49</sub>H<sub>55</sub>N<sub>9</sub>O<sub>7</sub> and a molecular weight of 882.035 g/mol. It is a highly flexible protein with 13 rotatable bonds. It has four hydrogen bond donors and nine hydrogen bond acceptors <ref>National Center for Biotechnology Inforamtion. PubChem Compound Database; CID=71661251, https://pubchem.ncbi.nlm.nih.gov/compound/71661251#section=Chemical-and-Physical-Properties</ref>. | ||
<Structure load='elbasvir.pdb' size='350' frame='true' align='right' caption='Elbasvir, a NS5A Inhibitor' scene='Elbasvir' /> | |||
Although the actual mechanism of Elbasvir as a NS5A inhibitor is unknown, several hypothetical mechanisms have been proposed. The NS5A protein is a critical protein for both DNA replication and assembly in the hepatitis C virus. With critical roles in both processes, NS5A is an excellent source as a target for inhibitors. NS5A is naturally located in the endoplasmic reticulum of the cell. When inhibited, the protein is redistributed from the ER to lipid droplets. If the cellular location changed, NS5A would be unable to aid in viral replication, illustrating a form of protein inhibition that Elbasvir could cause. Another potential mechanism of NS5A inhibitors is the altering of the phosphorylation of the NS5A protein <ref>DOI: http://dx.doi.org/10.1016/j.jhep.2013.03.030</ref>. The function of the NS5A protein is highly dependent on the phosphorylation, both basal phosphorylation and hyperphosphorylation <ref>doi: 10.1128/JVI.00253-11</ref>. Since the phosphorylation of the NS5A protein is critical for protein function, altering the levels of phosphorylation could impact the activity of the protein. | Although the actual mechanism of Elbasvir as a NS5A inhibitor is unknown, several hypothetical mechanisms have been proposed. The NS5A protein is a critical protein for both DNA replication and assembly in the hepatitis C virus. With critical roles in both processes, NS5A is an excellent source as a target for inhibitors. NS5A is naturally located in the endoplasmic reticulum of the cell. When inhibited, the protein is redistributed from the ER to lipid droplets. If the cellular location changed, NS5A would be unable to aid in viral replication, illustrating a form of protein inhibition that Elbasvir could cause. Another potential mechanism of NS5A inhibitors is the altering of the phosphorylation of the NS5A protein <ref>DOI: http://dx.doi.org/10.1016/j.jhep.2013.03.030</ref>. The function of the NS5A protein is highly dependent on the phosphorylation, both basal phosphorylation and hyperphosphorylation <ref>doi: 10.1128/JVI.00253-11</ref>. Since the phosphorylation of the NS5A protein is critical for protein function, altering the levels of phosphorylation could impact the activity of the protein. | ||
