View source for 6nzt


==Crystal structure of HCV NS3/4A protease in complex with voxilaprevir==
<StructureSection load='6nzt' size='340' side='right'caption='[[6nzt]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6nzt]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepacivirus_C Hepacivirus C]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NZT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NZT FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L9P:Voxilaprevir'>L9P</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6nzt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nzt OCA], [https://pdbe.org/6nzt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nzt RCSB], [https://www.ebi.ac.uk/pdbsum/6nzt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nzt ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/S4UY05_9HEPC S4UY05_9HEPC] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Treatment of hepatitis C virus (HCV) infection has been historically challenging due the high viral genetic complexity wherein there are eight distinct genotypes and at least 86 viral subtypes. While HCV NS3/4A protease inhibitors are an established treatment option for genotype 1 infection, limited coverage of genotypes 2 and/or 3 combined with serum alanine transaminase (ALT) elevations for some compounds has limited the broad utility of this therapeutic class. Our discovery efforts were focused on identifying an NS3/4A protease inhibitor with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. Towards this goal, distinct interactions with the conserved catalytic triad of the NS3/4A protease were identified that improved genotype 3 antiviral activity. We further discovered that protein adduct formation strongly correlated with clinical ALT elevation for this therapeutic class. Improving metabolic stability and decreasing protein adduct formation through structural modifications ultimately resulted in voxilaprevir. Voxilaprevir, in combination with sofosbuvir and velpatasvir, has demonstrated pan-genotypic antiviral clinical activity. Furthermore, hepatotoxicity was not observed in Phase 3 clinical trials with voxilaprevir, consistent with our design strategy. Vosevi((R)) (sofosbuvir, velpatasvir, and voxilaprevir) is now an approved pan-genotypic treatment option for the most difficult-to-cure individuals who have previously failed direct acting antiviral therapy.

Discovery of the pan-genotypic hepatitis C virus NS3/4A protease inhibitor voxilaprevir (GS-9857): A component of Vosevi((R)).,Taylor JG, Zipfel S, Ramey K, Vivian R, Schrier A, Karki KK, Katana A, Kato D, Kobayashi T, Martinez R, Sangi M, Siegel D, Tran CV, Yang ZY, Zablocki J, Yang CY, Wang Y, Wang K, Chan K, Barauskas O, Cheng G, Jin D, Schultz BE, Appleby T, Villasenor AG, Link JO Bioorg Med Chem Lett. 2019 Mar 26. pii: S0960-894X(19)30178-7. doi:, 10.1016/j.bmcl.2019.03.037. PMID:31133531<ref>PMID:31133531</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6nzt" style="background-color:#fffaf0;"></div>

==See Also==
*[[Virus protease 3D structures|Virus protease 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Hepacivirus C]]
[[Category: Large Structures]]
[[Category: Appleby TC]]
[[Category: Taylor JG]]