CoMFA and CoMSIA models were constructed through the partial least square (PLS) analysis using previously described neuraminidase inhibitors [102] . The optimal number of components was obtained from leave-one-out method to yield the highest r 2 and q 2 values in non-cross validation and cross-validation, respectively. Biological activities of the TCM de novo compounds were evaluated based on contour to the generated 3D-QSAR map. Table 6 . HA mutation points between the 1918 H1N1 and H1N1/09 viruses. Table 7 . NA mutation points between 1918 H1N1 and H1N1/09 viruses. Supporting Information  Synthesis of an antiviral drug precursor from chitin using a saprophyte as a whole-cell catalyst BACKGROUND: Recent incidents, such as the SARS and influenza epidemics, have highlighted the need for readily available antiviral drugs. One important precursor currently used for the production of Relenza, an antiviral product from GlaxoSmithKline, is N-acetylneuraminic acid (NeuNAc). This substance has a considerably high market price despite efforts to develop cost-reducing (biotechnological) production processes. Hypocrea jecorina (Trichoderma reesei) is a saprophyte noted for its abundant secretion of hydrolytic enzymes and its potential to degrade chitin to its monomer N-acetylglucosamine (GlcNAc). Chitin is considered the second most abundant biomass available on earth and therefore an attractive raw material. RESULTS: In this study, we introduced two enzymes from bacterial origin into Hypocrea, which convert GlcNAc into NeuNAc via N-acetylmannosamine. This enabled the fungus to produce NeuNAc from the cheap starting material chitin in liquid culture. Furthermore, we expressed the two recombinant enzymes as GST-fusion proteins and developed an enzyme assay for monitoring their enzymatic functionality. Finally, we demonstrated that Hypocrea does not metabolize NeuNAc and that no NeuNAc-uptake by the fungus occurs, which are important prerequisites for a potential production strategy. CONCLUSIONS: This study is a proof of concept for the possibility to engineer in a filamentous fungus a bacterial enzyme cascade, which is fully functional. Furthermore, it provides the basis for the development of a process for NeuNAc production as well as a general prospective design for production processes that use saprophytes as whole-cell catalysts. NeuNAc is the most prevalent exponent of sialic acids [1] . In mammals, sialic acids are usually found as terminal residues of glycol conjugates on the outermost cell surface. As a result of their location and their negative carboxylate functionality, sialic acids play important roles in mediating cellular recognition and adhesion processes [2] and in the infection cycles of severe viral diseases, such as influenza viruses A and B [3] . In these cases, de novo-synthesized viral particles attach to their respective sialic acids at the cell surface. Neuraminidase (sialidase) activity is needed for the propagation of the virus in the host. Consequently, sialic acid derivatives are successfully applied in the therapy of such virus-related diseases. One well-known product that functions as a neuraminidase inhibitor is Relenza. Its active pharmaceutical ingredient is Zanamivir, which is a direct derivative of the NeuNAc precursor [4] .