4P1U

Influenza A (flu) virus polymerase basic protein 2 (PB2) bound to VX787, an azaindole inhibitor

Summary for 4P1U

• Entry DOI: 10.2210/pdb4p1u/pdb
• Descriptor: Polymerase basic protein 2, (2S,3S)-3-[[5-fluoranyl-2-(5-fluoranyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]bicyclo[2.2.2]octane-2-carboxylic acid (3 entities in total)
• Functional Keywords: small-molecule drug, inhibitor, flu, m7-gtp pocket, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Influenza A virus
• Cellular location: Virion: P31345
• Total number of polymer chains: 1
• Total formula weight: 19573.72

Authors

Jacobs, M.D. (deposition date: 2014-02-27, release date: 2014-07-30, Last modification date: 2023-12-27)

Primary citation

Clark, M.P.,Ledeboer, M.W.,Davies, I.,Byrn, R.A.,Jones, S.M.,Perola, E.,Tsai, A.,Jacobs, M.,Nti-Addae, K.,Bandarage, U.K.,Boyd, M.J.,Bethiel, R.S.,Court, J.J.,Deng, H.,Duffy, J.P.,Dorsch, W.A.,Farmer, L.J.,Gao, H.,Gu, W.,Jackson, K.,Jacobs, D.H.,Kennedy, J.M.,Ledford, B.,Liang, J.,Maltais, F.,Murcko, M.,Wang, T.,Wannamaker, M.W.,Bennett, H.B.,Leeman, J.R.,McNeil, C.,Taylor, W.P.,Memmott, C.,Jiang, M.,Rijnbrand, R.,Bral, C.,Germann, U.,Nezami, A.,Zhang, Y.,Salituro, F.G.,Bennani, Y.L.,Charifson, P.S.
Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2.
J.Med.Chem., 57:6668-6678, 2014

PubMed Abstract: In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.

PubMed: 25019388
DOI: 10.1021/jm5007275

Experimental method

X-RAY DIFFRACTION (2.52 Å)