Zepatier: Difference between revisions
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<scene name='74/745998/Elbasvir_structure1/7'>Elbasvir</scene>, MK-8742,a tetra-cyclic <scene name='74/746120/Indole_elbasvir/3'>indole</scene> 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 continued development of compounds 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 name="elbasvir" />. 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>. | <scene name='74/745998/Elbasvir_structure1/7'>Elbasvir</scene>, MK-8742,a tetra-cyclic <scene name='74/746120/Indole_elbasvir/3'>indole</scene> 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 continued development of compounds 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 name="elbasvir" />. 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>. | ||
Although the actual mechanism of Elbasvir as a NS5A inhibitor is unknown, several hypothetical mechanisms have been proposed. The NS5A protein is critical 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 located within 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 caused by Elbasvir. Another potential mechanism of NS5A inhibitors is the altering of the phosphorylation of the NS5A protein <ref> | Although the actual mechanism of Elbasvir as a NS5A inhibitor is unknown, several hypothetical mechanisms have been proposed. The NS5A protein is critical 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 located within 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 caused by Elbasvir. Another potential mechanism of NS5A inhibitors is the altering of the phosphorylation of the NS5A protein <ref>http://dx.doi.org/10.1016/j.jhep.2013.03.030 | ||
</ref>. The function of the NS5A protein is highly dependent on basal and hyperphosphorylation phosphorylation <ref>doi: 10.1128/JVI.00253-11</ref>. Since the phosphorylation of the NS5A protein is critical for protein function, altering levels of phosphorylation could impact activity of the protein. | </ref>. The function of the NS5A protein is highly dependent on basal and hyperphosphorylation phosphorylation <ref>doi: 10.1128/JVI.00253-11</ref>. Since the phosphorylation of the NS5A protein is critical for protein function, altering levels of phosphorylation could impact activity of the protein. | ||
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<ref name="elbasvir">DOI: 10.1002/cmdc.201300343</ref> | <ref name="elbasvir">DOI: 10.1002/cmdc.201300343</ref> | ||
<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> | <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> | ||
<ref>doi: 10.1128/JVI.00253-11</ref> | <ref>doi: 10.1128/JVI.00253-11</ref> | ||
<ref>Chevaliez, S.; Pawlotsky, J. M. Virology of hepatitis C virus infection. Best Pract. Res. Clin. Gastroenterol.2012, 26, 381-389.</ref> | <ref>Chevaliez, S.; Pawlotsky, J. M. Virology of hepatitis C virus infection. Best Pract. Res. Clin. Gastroenterol.2012, 26, 381-389.</ref> | ||
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<ref>National Center for Biotechnology Information. PubChem Compound Database; CID=44603531, https://pubchem.ncbi.nlm.nih.gov/compound/44603531.</ref> | <ref>National Center for Biotechnology Information. PubChem Compound Database; CID=44603531, https://pubchem.ncbi.nlm.nih.gov/compound/44603531.</ref> | ||
<ref>DOI: 10.1021/acschembio.5b00647</ref> | <ref>DOI: 10.1021/acschembio.5b00647</ref> | ||
<ref>Tan, S.-L. Hepatitis C viruses: genomes and molecular biology; Horizon bioscience: Wymondham, 2006. | <ref>Tan, S.-L. Hepatitis C viruses: genomes and molecular biology; Horizon bioscience: Wymondham, 2006. </ref> | ||
<ref> | <ref>http://dx.doi.org/10.1016/j.jhep.2013.03.030</ref> | ||
</ref> | |||
