View source for 9thj


==Crystal structure of H5N1 influenza polymerase PB2 domain in complex with compound 3==
<StructureSection load='9thj' size='340' side='right'caption='[[9thj]], [[Resolution|resolution]] 0.91&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9thj]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_A_virus_(A/duck/Shantou/4610/2003(H5N1)) Influenza A virus (A/duck/Shantou/4610/2003(H5N1))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9THJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9THJ 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]] 0.91&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JV9:(1~{R},2~{S},4~{R},5~{S},6~{S},7~{S})-7-[[5-fluoranyl-2-(5-fluoranyl-1~{H}-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl]amino]tricyclo[3.2.2.0^{2,4}]nonane-6-carboxylic+acid'>A1JV9</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=9thj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9thj OCA], [https://pdbe.org/9thj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9thj RCSB], [https://www.ebi.ac.uk/pdbsum/9thj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9thj ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q2LG68_IH5N1 Q2LG68_IH5N1] Plays an essential role in transcription initiation and cap-stealing mechanism, in which cellular capped pre-mRNAs are used to generate primers for viral transcription. Recognizes and binds the 7-methylguanosine-containing cap of the target pre-RNA which is subsequently cleaved after 10-13 nucleotides by the viral protein PA. Plays a role in the initiation of the viral genome replication and modulates the activity of the ribonucleoprotein (RNP) complex. In addition, participates in the inhibition of type I interferon induction through interaction with and inhibition of the host mitochondrial antiviral signaling protein MAVS.[ARBA:ARBA00054053]
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== Publication Abstract from PubMed ==
In pursuit of potent, efficacious influenza inhibitors with novel mechanisms, we replaced the 7-azaindole core of the PB2 inhibitor pimodivir (VX-787/JNJ872) with a 7-fluoro-substituted indazole to mitigate CYP3A- and aldehyde oxidase-mediated metabolism by lowering lipophilicity and blocking the metabolic soft spot. We further introduced a cyclopropyl-fused ring onto the bridged bicyclo[2.2.2]-octane to retain potency while reducing glucuronidation. This design converged in compound 3, where the indazole scaffold and fused cyclopropyl ring acted synergistically to improve the potency and pharmacokinetic properties. In a lethal influenza mouse challenge model, compound 3 achieved approximately a 7-fold reduction in the effective dose compared with pimodivir. It also showed significantly improved activity against selected influenza A strains versus pimodivir, highlighting its potential as a differentiated PB2 inhibitor.

Discovery of Potent and Efficacious Influenza PB2 Inhibitors.,Wu J, Liu Y, Li D, Wang L, Neidhart W, Chen B, Hochstrasser R, Kuglstatter A, Gasser R, Qiu H, Shi T, Chao SK, Gao J, Shen HC, Tan X ACS Med Chem Lett. 2025 Dec 12;17(1):249-256. doi: , 10.1021/acsmedchemlett.5c00674. eCollection 2026 Jan 8. PMID:41531980<ref>PMID:41531980</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9thj" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Ehler A]]
[[Category: Kuglstatter A]]