4MK1

5-bromopyridine-2,3-diol bound to influenza 2009 pH1N1 endonuclease

Summary for 4MK1

• Entry DOI: 10.2210/pdb4mk1/pdb
• Related: 4LN7 4M4Q 4M5O 4M5Q 4M5R 4M5V 4MK2 4MK5
• Descriptor: POLYMERASE PA, MANGANESE (II) ION, SULFATE ION, ... (6 entities in total)
• Functional Keywords: cap-snatching, rna binding protein, rna binding protein-inhibitor complex, rna binding protein/inhibitor
• Biological source: INFLUENZA A VIRUS (A/LIMA/WRAIR1695P/2009(H1N1))
• Total number of polymer chains: 1
• Total formula weight: 29453.14

Authors

Bauman, J.D.,Patel, D.,Das, K.,Arnold, E. (deposition date: 2013-09-04, release date: 2013-09-25, Last modification date: 2024-02-28)

Primary citation

Bauman, J.D.,Patel, D.,Baker, S.F.,Vijayan, R.S.,Xiang, A.,Parhi, A.K.,Martinez-Sobrido, L.,Lavoie, E.J.,Das, K.,Arnold, E.
Crystallographic fragment screening and structure-based optimization yields a new class of influenza endonuclease inhibitors.
Acs Chem.Biol., 8:2501-2508, 2013

PubMed Abstract: Seasonal and pandemic influenza viruses continue to be a leading global health concern. Emerging resistance to the current drugs and the variable efficacy of vaccines underscore the need for developing new flu drugs that will be broadly effective against wild-type and drug-resistant influenza strains. Here, we report the discovery and development of a class of inhibitors targeting the cap-snatching endonuclease activity of the viral polymerase. A high-resolution crystal form of pandemic 2009 H1N1 influenza polymerase acidic protein N-terminal endonuclease domain (PAN) was engineered and used for fragment screening leading to the identification of new chemical scaffolds binding to the PAN active site cleft. During the course of screening, binding of a third metal ion that is potentially relevant to endonuclease activity was detected in the active site cleft of PAN in the presence of a fragment. Using structure-based optimization, we developed a highly potent hydroxypyridinone series of compounds from a fragment hit that defines a new mode of chelation to the active site metal ions. A compound from the series demonstrating promising enzymatic inhibition in a fluorescence-based enzyme assay with an IC50 value of 11 nM was found to have an antiviral activity (EC50) of 11 μM against PR8 H1N1 influenza A in MDCK cells.

PubMed: 23978130
DOI: 10.1021/cb400400j

Experimental method

X-RAY DIFFRACTION (1.85 Å)