7e6q: Difference between revisions
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==Crystal structure of influenza A virus neuraminidase N5 complexed with 4'-phenyl-1,2,3-triazolylated oseltamivir carboxylate== | ==Crystal structure of influenza A virus neuraminidase N5 complexed with 4'-phenyl-1,2,3-triazolylated oseltamivir carboxylate== | ||
<StructureSection load='7e6q' size='340' side='right'caption='[[7e6q]]' scene=''> | <StructureSection load='7e6q' size='340' side='right'caption='[[7e6q]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7E6Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E6Q FirstGlance]. <br> | <table><tr><td colspan='2'>[[7e6q]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/I76a2 I76a2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7E6Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E6Q FirstGlance]. <br> | ||
</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=7e6q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e6q OCA], [https://pdbe.org/7e6q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e6q RCSB], [https://www.ebi.ac.uk/pdbsum/7e6q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e6q ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=HZF:(3R,4R,5S)-4-acetamido-3-pentan-3-yloxy-5-(4-phenyl-1,2,3-triazol-1-yl)cyclohexene-1-carboxylic+acid'>HZF</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NA ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=385582 I76A2])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Exo-alpha-sialidase Exo-alpha-sialidase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.18 3.2.1.18] </span></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=7e6q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e6q OCA], [https://pdbe.org/7e6q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e6q RCSB], [https://www.ebi.ac.uk/pdbsum/7e6q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e6q ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Resistant viruses containing mutant neuraminidases (NAs) with diminished drug affinity continue to emerge, and new anti-influenza agents are urgently required. Several potent inhibitors targeting the hydrophobic 150-cavity of viral NAs have been developed by modifying the antiviral drugs, oseltamivir carboxylate (OSC) and zanamivir, with hydrophobic groups. Here, we describe a different strategy for exploring novel and efficient NA inhibitors by targeting the charged amino acid residues around the entrance to the 150-cavity. We synthesized a C5-substituted OSC derivative (1e) with a 4'-phenyl-1,2,3-triazolyl group capable of entering the 150-cavity, and solved the crystal structure of 1e in complex with influenza A virus N5 NA. Using the resulting structural information, we next designed and synthesized two series of OSC derivatives carrying various polar substituents at the triazolyl group of 1e and 2e, with 2e being a 5'-phenyl-1,2,3-triazole regioisomer of 1e. The NA inhibition assays demonstrated that the 2 series (2e-n) generally had superior activity compared with the 1 series (1e-n). Compound 2j, bearing a 3-phenylamino group on the triazole ring, was the most potent inhibitor of all tested NAs including an N2 NA containing the E119V OSC-resistant mutation. Moreover, 2j potently inhibited viral replication in vitro, and molecular docking studies revealed that its phenylamino group can form an additional strong hydrogen bond with residue D151 near the entrance of the 150-cavity. The design method described in this study provides useful insights into the development of novel NA inhibitors. Compound 2j warrants further structural optimization to obtain a candidate for clinical use. | |||
Structure-based design of 5'-substituted 1,2,3-triazolylated oseltamivir derivatives as potent influenza neuraminidase inhibitors.,Wang P, Oladejo BO, Li C, Fu L, Zhang S, Qi J, Lv X, Li X RSC Adv. 2021 Mar 3;11(16):9528-9541. doi: 10.1039/d1ra00472g. eCollection 2021, Mar 1. PMID:35423449<ref>PMID:35423449</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7e6q" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Neuraminidase 3D structures|Neuraminidase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Exo-alpha-sialidase]] | |||
[[Category: I76a2]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Babayemi | [[Category: Babayemi, O O]] | ||
[[Category: Fu | [[Category: Fu, L F]] | ||
[[Category: Li | [[Category: Li, C N]] | ||
[[Category: Li | [[Category: Li, X B]] | ||
[[Category: Lv X]] | [[Category: Lv, X]] | ||
[[Category: Qi | [[Category: Qi, J X]] | ||
[[Category: Wang | [[Category: Wang, P F]] | ||
[[Category: Zhang | [[Category: Zhang, S S]] | ||
[[Category: 150-cavity]] | |||
[[Category: Hydrolase]] | |||
[[Category: Influenza virus]] | |||
[[Category: Neuraminidase inhibitor]] | |||
[[Category: Oseltamivir derivative]] | |||
Revision as of 08:15, 15 June 2022
Crystal structure of influenza A virus neuraminidase N5 complexed with 4'-phenyl-1,2,3-triazolylated oseltamivir carboxylateCrystal structure of influenza A virus neuraminidase N5 complexed with 4'-phenyl-1,2,3-triazolylated oseltamivir carboxylate
Structural highlights
Publication Abstract from PubMedResistant viruses containing mutant neuraminidases (NAs) with diminished drug affinity continue to emerge, and new anti-influenza agents are urgently required. Several potent inhibitors targeting the hydrophobic 150-cavity of viral NAs have been developed by modifying the antiviral drugs, oseltamivir carboxylate (OSC) and zanamivir, with hydrophobic groups. Here, we describe a different strategy for exploring novel and efficient NA inhibitors by targeting the charged amino acid residues around the entrance to the 150-cavity. We synthesized a C5-substituted OSC derivative (1e) with a 4'-phenyl-1,2,3-triazolyl group capable of entering the 150-cavity, and solved the crystal structure of 1e in complex with influenza A virus N5 NA. Using the resulting structural information, we next designed and synthesized two series of OSC derivatives carrying various polar substituents at the triazolyl group of 1e and 2e, with 2e being a 5'-phenyl-1,2,3-triazole regioisomer of 1e. The NA inhibition assays demonstrated that the 2 series (2e-n) generally had superior activity compared with the 1 series (1e-n). Compound 2j, bearing a 3-phenylamino group on the triazole ring, was the most potent inhibitor of all tested NAs including an N2 NA containing the E119V OSC-resistant mutation. Moreover, 2j potently inhibited viral replication in vitro, and molecular docking studies revealed that its phenylamino group can form an additional strong hydrogen bond with residue D151 near the entrance of the 150-cavity. The design method described in this study provides useful insights into the development of novel NA inhibitors. Compound 2j warrants further structural optimization to obtain a candidate for clinical use. Structure-based design of 5'-substituted 1,2,3-triazolylated oseltamivir derivatives as potent influenza neuraminidase inhibitors.,Wang P, Oladejo BO, Li C, Fu L, Zhang S, Qi J, Lv X, Li X RSC Adv. 2021 Mar 3;11(16):9528-9541. doi: 10.1039/d1ra00472g. eCollection 2021, Mar 1. PMID:35423449[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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