Due to the association of human papillomaviruses (HPV) with development of multiple carcinomas, especially cervical carcinomas, early diagnosis and prevention of infection with HPV are of great medical and economic importance. Knowledge of the early steps of papillomavirus infection, which results in infectious entry, will help develop means to prevent HPV-induced lesions. Since HPV are difficult to propagate in cell culture, surrogate infection systems with marker-encoding viral capsids, called HPV pseudovirions, have been developed and successfully used in investigating the HPV entry pathway as well as in testing of substances interfering with HPV infection (2, 33). These studies have led to the identification of specifically modified heparan sulfate proteoglycans (HSPGs) as primary attachment receptors for papillomaviruses (13,15) and to heparin and other sulfated polysaccharides as inhibitors of HPV infection (1, 7, 13). Recently, carrageenan, an unbranched sulfated polysaccharide from algae with saccharide linkages reminiscent of galactosaminoglycans, has been reported to inhibit HPV infection primarily by preventing the binding of virions to the cell (4). Dispirotripiperazine (DSTP) derivatives represent another substance class with proven antiviral potential. DSTP27 (an N,NЈ-bisheteryl derivative of DSTP), one of the most active derivatives of this new class of low-molecular-weight antiherpetic compounds, interacts with specific forms of cell surface HSPGs (26). In addition to the inhibition of herpes virus attachment and infection, DSTP27 efficiently blocks the attachment and uptake of members from other virus families that depend on HSPGs as primary attachment molecules (25). In contrast to the HS analogs such as heparin and pentosan polysulfate that have short-lived effects, pretreatment of cells with DSTP27 induces a longlasting antiviral effect. Based on computer modeling, DSTP27 possibly interacts with two O-sulfate groups located on neighboring saccharides of the HS chain (27). Using the octosaccharide essential for HS-mediated entry of herpes simplex virus type 1 (HSV-1) into host cells (20), these computational studies further show that DSTP27 may additionally interact with a carbonyl group, thus increasing the strength of compound binding.Since HPV bind specifically to sulfated polysaccharide residues of cell surface HSPGs, particularly 2-O-and 6-O-sulfated HS chains in addition to N-sulfated residues (27), DSTP27 was predicted to work as a potent inhibitor of HPV infection. In this report we demonstrate that DSTP27 efficiently prevents HPV infection when applied several hours pre-or postinfection of cells. This is achieved by two putatively different mech-* Corresponding author. Mailing address:

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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 (2000-2011), 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.

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At present, neuraminidase (NA) inhibitors are the mainstay of pharmacological strategies to fight against global pandemic influenza. In the search for new antiviral drug leads from nature, the seed extract of Alpinia katsumadai has been phytochemically investigated. Among the six isolated constituents, four diarylheptanoids showed in vitro NA inhibitory activities in low micromolar ranges against human influenza virus A/PR/8/34 of subtype H1N1. The most promising constituent, katsumadain A (4; IC(50) = 1.05 +/- 0.42 microM), also inhibited the NA of four H1N1 swine influenza viruses, with IC(50) values between 0.9 and 1.64 muM, and showed antiviral effects in plaque reduction assays. Considering the flexible loop regions of NA, extensive molecular dynamics (MD) simulations were performed to study the putative binding mechanism of the T-shaped diarylheptanoid 4. Docking results showed well-established interactions between the protein and the core of this novel NA-inhibiting natural scaffold, excellent surface complementarity to the simulated binding pocket, and concordance with experimentally derived SAR data.