4yd0
From Proteopedia
Influenza polymerase basic protein 2 (PB2) bound to an azaindole-tetrazole inhibitor
Structural highlights
FunctionPB2_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 PubMedVX-787 is a first in class, orally bioavailable compound that offers unparalleled potential for the treatment of pandemic and seasonal influenza. As a part of our routine SAR exploration, carboxylic acid isosteres of VX-787 were prepared and tested against influenza A. It was found that the negative charge is important for maintaining potency and selectivity relative to kinase targets. Neutral carboxylic acid replacements generally resulted in compounds that were significantly less potent and less selective relative to the charged species. Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors.,Boyd MJ, Bandarage UK, Bennett H, Byrn RR, Davies I, Gu W, Jacobs M, Ledeboer MW, Ledford B, Leeman JR, Perola E, Wang T, Bennani Y, Clark MP, Charifson PS Bioorg Med Chem Lett. 2015 Mar 14. pii: S0960-894X(15)00209-7. doi:, 10.1016/j.bmcl.2015.03.013. PMID:25827523[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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