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Molecules 2017, 22(11), 1989; doi:10.3390/molecules22111989

Different Inhibitory Potencies of Oseltamivir Carboxylate, Zanamivir, and Several Tannins on Bacterial and Viral Neuraminidases as Assessed in a Cell-Free Fluorescence-Based Enzyme Inhibition Assay

1
Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany
2
Max-Delbrück-Centrum for Molecular Medicine, Helmholtz Protein Sample Production Facility, Robert-Rössle-Str. 10, 13125 Berlin, Germany
These authors share last authorship.
*
Author to whom correspondence should be addressed.
Received: 23 October 2017 / Revised: 14 November 2017 / Accepted: 15 November 2017 / Published: 17 November 2017
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Abstract

Neuraminidase is a key enzyme in the life cycle of influenza viruses and is present in some bacterial pathogens. We here assess the inhibitory potency of plant tannins versus clinically used inhibitors on both a viral and a bacterial model neuraminidase by applying the 2′-(4-methylumbelliferyl)-α-d-N-acetylneuraminic acid (MUNANA)-based activity assay. A range of flavan-3-ols, ellagitannins and chemically defined proanthocyanidin fractions was evaluated in comparison to oseltamivir carboxylate and zanamivir for their inhibitory activities against viral influenza A (H1N1) and bacterial Vibrio cholerae neuraminidase (VCNA). Compared to the positive controls, all tested polyphenols displayed a weak inhibition of the viral enzyme but similar or even higher potency on the bacterial neuraminidase. Structure–activity relationship analyses revealed the presence of galloyl groups and the hydroxylation pattern of the flavan skeleton to be crucial for inhibitory activity. The combination of zanamivir and EPs® 7630 (root extract of Pelargonium sidoides) showed synergistic inhibitory effects on the bacterial neuraminidase. Co-crystal structures of VCNA with oseltamivir carboxylate and zanamivir provided insight into bacterial versus viral enzyme-inhibitor interactions. The current data clearly indicate that inhibitor potency strongly depends on the biological origin of the enzyme and that results are not readily transferable. The therapeutic relevance of our findings is briefly discussed. View Full-Text
Keywords: neuraminidase; inhibition; tannins; oseltamivir carboxylate; zanamivir; crystal structure; molecular interactions neuraminidase; inhibition; tannins; oseltamivir carboxylate; zanamivir; crystal structure; molecular interactions
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Quosdorf, S.; Schuetz, A.; Kolodziej, H. Different Inhibitory Potencies of Oseltamivir Carboxylate, Zanamivir, and Several Tannins on Bacterial and Viral Neuraminidases as Assessed in a Cell-Free Fluorescence-Based Enzyme Inhibition Assay. Molecules 2017, 22, 1989.

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