Abstract
The part of the influenza polymerase PA subunit featuring endonuclease activity is a target for anti-influenza therapies, including the FDA-approved drug Xofluza. A general feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions located in the enzyme’s catalytic site. Previously, we screened a panel of flavonoids for PA inhibition and found luteolin and its C-glucoside orientin to be potent inhibitors. Through structural analysis, we identified the presence of a 3′,4′-dihydroxyphenyl moiety as a crucial feature for sub-micromolar inhibitory activity. Here, we report results from a subsequent investigation exploring structural changes at the C-7 and C-8 positions of luteolin. Experimental IC50 values were determined by AlphaScreen technology. The most potent inhibitors were C-8 derivatives with inhibitory potencies comparable to that of luteolin. Bio-isosteric replacement of the C-7 hydroxyl moiety of luteolin led to a series of compounds with one-order-of-magnitude-lower inhibitory potencies. Using X-ray crystallography, we solved structures of the wild-type PA-N-terminal domain and its I38T mutant in complex with orientin at 1.9 Å and 2.2 Å resolution, respectively.
Highlights
Influenza viruses cause illness in a variety of species, including humans
We developed a screening assay based on AlphaScreen technology and determined the inhibitory potency of 38 flavonoids, of which luteolin (IC50 of 73 ± 3 nM) and its 8-C-glucoside orientin (IC50 of 42 ± 2 nM) were the most potent inhibitors (Figure 1)
Preparation of this C-7 series started from luteolin, which was per-acetylated
Summary
Influenza viruses cause illness in a variety of species, including humans. Despite the availability of vaccines and antiviral drugs, influenza remains a serious threat to human health, causing 290,000–650,000 deaths worldwide annually [1]. RNA-dependent RNA polymerase (RdRP) lacks proof-reading activity, which leads to an accumulation of point mutations known as antigenic drift. This is responsible for the emergence of new viral variants causing seasonal flu, which requires the flu vaccine to be reformulated every year. Antigenic shift—the reassortment of viral RNA segments from two or more different influenza strains in animals or humans—could lead to a new pandemic strain. Vaccination is the best intervention against viral pathogens including influenza. The intricacies of vaccine development, in combination with influenza’s genomic variability, makes the development of novel anti-influenza therapeutics imperative
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