5f79

Influenza PB2 bound to an azaindole inhibitor

spinqualitylabelsall models 5f79, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5f79 is a 1 chain structure with sequence from I75a0. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 4V7 Gene: PB2 (I75A0) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [PB2_I75A0] 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. Binds the cap of the target pre-RNA which is subsequently cleaved after 10-13 nucleotides by 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 the host mitochondrial antiviral signaling protein MAVS.[UniProtKB:P03428] Publication Abstract from PubMed JNJ-63623872 (2) is a first-in-class, orally bioavailable compound that offers significant potential for the treatment of pandemic and seasonal influenza. Early lead optimization efforts in our 7-azaindole series focused on 1,3-diaminocyclohexyl amide and urea substitutions on the pyrimidine-7-azaindole motif. In this work, we explored two strategies to eliminate observed aldehyde oxidase (AO)-mediated metabolism at the 2-position of these 7-azaindole analogues. Substitution at the 2-position of the azaindole ring generated somewhat less potent analogues, but reduced AO-mediated metabolism. Incorporation of a ring nitrogen generated 7-azaindazole analogues that were equipotent to the parent 2-H-7-azaindole, but surprisingly, did not appear to improve AO-mediated metabolism. Overall, we identified multiple 2-substituted 7-azaindole analogues with enhanced AO stability and we present data for one such compound (12) that demonstrate a favorable oral pharmacokinetic profile in rodents. These analogues have the potential to be further developed as anti-influenza agents for the treatment of influenza. Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza.,Bandarage UK, Clark MP, Perola E, Gao H, Jacobs MD, Tsai A, Gillespie J, Kennedy JM, Maltais F, Ledeboer MW, Davies I, Gu W, Byrn RA, Nti Addae K, Bennett H, Leeman JR, Jones SM, O'Brien C, Memmott C, Bennani Y, Charifson PS ACS Med Chem Lett. 2017 Jan 18;8(2):261-265. doi: 10.1021/acsmedchemlett.6b00487., eCollection 2017 Feb 9. PMID:28197323 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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