Influenza neuraminidase: A druggable target for natural products

• Published in: Natural Product Reports 2012-01, Vol.29 (1), p.11-36
• Main Authors: Grienke, Ulrike, Schmidtke, Michaela, von Grafenstein, Susanne, Kirchmair, Johannes, Liedl, Klaus R, Rollinger, Judith M
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological Products - chemistry; Biological Products - pharmacology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Influenza A Virus, H1N1 Subtype - drug effects; Influenza Vaccines - pharmacology; Influenza, Human - classification; Influenza, Human - drug therapy; Molecular Structure; Neuraminidase - antagonists & inhibitors; Neuraminidase - chemistry; Neuraminidase - drug effects; Terpenes - chemistry; Terpenes - pharmacology
• ISSN: 0265-0568; 1460-4752
• DOI: 10.1039/c1np00053e

Covering: 2000 to 2011 The imminent threat of influenza pandemics and repeatedly reported emergence of new drug-resistant influenza virus strains demonstrate the urgent need for developing innovative and effective antiviral agents for prevention and treatment. At present, influenza neuraminidase (NA), a key enzyme in viral replication, spread, and pathogenesis, is considered to be one of the most promising targets for combating influenza. Despite the substantial medical potential of NA inhibitors (NAIs), only three of these drugs are currently on the market (zanamivir, oseltamivir, and peramivir). Moreover, sudden changes in NAI susceptibility revealed the urgent need in the discovery/identification of novel inhibitors. Nature offers an abundance of biosynthesized compounds comprising chemical scaffolds of high diversity, which present an infinite pool of chemical entities for target-oriented drug discovery in the battle against this highly contagious pathogen. This review illuminates the increasing research efforts of the past decade (20002011), focusing on the structure, function and druggability of influenza NA, as well as its inhibition by natural products. Following a critical discussion of publications describing some 150 secondary plant metabolites tested for their inhibitory potential against influenza NA, the impact of three different strategies to identify and develop novel NAIs is presented: (i) bioactivity screening of herbal extracts, (ii) exploitation of empirical knowledge, and (iii) computational approaches. This work addresses the latest developments in theoretical and experimental research on properties of NA that are and will be driving anti-influenza drug development now and in the near future. This review covers the increasing research efforts of the past decade, focusing on the structure, function and druggability of influenza NA, and its inhibition by natural products. Latest developments in theoretical and experimental research on NA for lead discovery strategies from nature are presented.