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.
Highlights
Influenza is an acute viral infection of the respiratory tract, afflicting millions of individuals each year
neuraminidase inhibitors (NAIs) oseltamivir carboxylate and zanamivir were included as reference compounds
To validate our assay conditions, we first assessed the inhibitory potency of the reference NAIs oseltamivir carboxylate and zanamivir (Figure 2) against both the viral influenza A/California/04/2009 (H1N1) neuraminidase (H1N1-NA) and the bacterial Vibrio cholerae neuraminidase (VCNA)
Summary
Influenza is an acute viral infection of the respiratory tract, afflicting millions of individuals each year. The therapeutic efficacy of M2 ion channel blockers such as amantadine and rimantadine is limited to influenza A viruses These therapeutics are associated with the rapid emergence of drug resistance and have the disadvantage of side effects. The approved NAIs oseltamivir, zanamivir, peramivir, and laninamivir are first choice antiviral drugs for the treatment of influenza A and B virus infections. Comparative studies on the effect of tannins on bacterial and viral NAs are lacking. These comparisons could allow for the evaluation of the therapeutic significance of bacterial enzyme inhibition data in the identification of anti-viral substances [3]. To provide a rationale for differential inhibition of bacterial and viral NAs, we performed X-ray crystallographic analyses of NAs in complex with the synthetic reference compounds oseltamivir carboxylate and zanamivir
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
