5JUN

PB2 bound to an azaindole inhibitor

Summary for 5JUN

• Entry DOI: 10.2210/pdb5jun/pdb
• Related: 5JUR
• Descriptor: Polymerase basic protein 2, (3~{R})-3-[[5-fluoranyl-2-(5-fluoranyl-1~{H}-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]-3-(1-methylcyclobutyl)propanoic acid (3 entities in total)
• Functional Keywords: flu, polymerase, nucleotide binding, inhibitor, rna binding protein
• Biological source: Influenza A virus
• Cellular location: Virion : Q30NP1
• Total number of polymer chains: 1
• Total formula weight: 19561.71

Authors

Jacobs, M.D. (deposition date: 2016-05-10, release date: 2017-05-17, Last modification date: 2023-09-27)

Primary citation

Farmer, L.J.,Clark, M.P.,Boyd, M.J.,Perola, E.,Jones, S.M.,Tsai, A.,Jacobs, M.D.,Bandarage, U.K.,Ledeboer, M.W.,Wang, T.,Deng, H.,Ledford, B.,Gu, W.,Duffy, J.P.,Bethiel, R.S.,Shannon, D.,Byrn, R.A.,Leeman, J.R.,Rijnbrand, R.,Bennett, H.B.,O'Brien, C.,Memmott, C.,Nti-Addae, K.,Bennani, Y.L.,Charifson, P.S.
Discovery of Novel, Orally Bioavailable beta-Amino Acid Azaindole Inhibitors of Influenza PB2.
ACS Med Chem Lett, 8:256-260, 2017

PubMed Abstract: In 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 β-amino acid inhibitors, highlighted by compound . Compound 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 offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.

PubMed: 28197322
DOI: 10.1021/acsmedchemlett.6b00486

Experimental method

X-RAY DIFFRACTION (2.69 Å)