Structural highlights
4m5u is a 1 chain structure with sequence from Influenza a virus (a/lima/wrair1695p/2009(h1n1)). Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , , |
| Related: | 4kil, 4ln7, 4m5o, 4m5q, 4m5r, 4m5v |
| Gene: | PA (Influenza A virus (A/Lima/WRAIR1695P/2009(H1N1))) |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Function
[F0TRT1_9INFA] Implicated in endonuclease cleavage of capped RNA primers. Displays an elongation factor activity in viral RNA synthesis. Dispensable for viral transcription, but not replication (By similarity).[SAAS:SAAS001009_004_020464]
Publication Abstract from PubMed
Inhibition of the endonuclease activity of influenza RNA-dependent RNA polymerase is recognized as an attractive target for the development of new agents for the treatment of influenza infection. Our earlier study employing small molecule fragment screening using a high-resolution crystal form of pandemic 2009 H1N1 influenza A endonuclease domain (PAN) resulted in the identification of 5-chloro-3-hydroxypyridin-2(1H)-one as a bimetal chelating ligand at the active site of the enzyme. In the present study, several phenyl substituted 3-hydroxypyridin-2(1H)-one compounds were synthesized and evaluated for their ability to inhibit the endonuclease activity as measured by a high-throughput fluorescence assay. Two of the more potent compounds in this series, 16 and 18, had IC50 values of 11 and 23nM in the enzymatic assay, respectively. Crystal structures revealed that these compounds had distinct binding modes that chelate the two active site metal ions (M1 and M2) using only two chelating groups. The SAR and the binding mode of these 3-hydroxypyridin-2-ones provide a basis for developing a new class of anti-influenza drugs.
Phenyl substituted 3-hydroxypyridin-2(1H)-ones: inhibitors of influenza A endonuclease.,Parhi AK, Xiang A, Bauman JD, Patel D, Vijayan RS, Das K, Arnold E, Lavoie EJ Bioorg Med Chem. 2013 Nov 1;21(21):6435-46. doi: 10.1016/j.bmc.2013.08.053. Epub , 2013 Sep 4. PMID:24055080[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Parhi AK, Xiang A, Bauman JD, Patel D, Vijayan RS, Das K, Arnold E, Lavoie EJ. Phenyl substituted 3-hydroxypyridin-2(1H)-ones: inhibitors of influenza A endonuclease. Bioorg Med Chem. 2013 Nov 1;21(21):6435-46. doi: 10.1016/j.bmc.2013.08.053. Epub , 2013 Sep 4. PMID:24055080 doi:http://dx.doi.org/10.1016/j.bmc.2013.08.053
