5jur
PB2 bound to an azaindole 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 PubMedIn our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic beta-amino acid inhibitors, highlighted by compound 4. Compound 4 showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound 4 offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza. Discovery of Novel, Orally Bioavailable beta-Amino Acid Azaindole Inhibitors of Influenza PB2.,Farmer LJ, Clark MP, Boyd MJ, Perola E, Jones SM, Tsai A, Jacobs MD, Bandarage UK, Ledeboer MW, Wang T, Deng H, Ledford B, Gu W, Duffy JP, Bethiel RS, Shannon D, Byrn RA, Leeman JR, Rijnbrand R, Bennett HB, O'Brien C, Memmott C, Nti-Addae K, Bennani YL, Charifson PS ACS Med Chem Lett. 2017 Jan 20;8(2):256-260. doi: 10.1021/acsmedchemlett.6b00486., eCollection 2017 Feb 9. PMID:28197322[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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