By nature, a challenge to siRNA-screening efforts is false negatives that derive from weak phenotypes due to suboptimal depletion of what are otherwise key factors in the biological process under investigation. One opportunity to help meet this challenge is to employ coherent behavior of gene sets to identify key biological processes supporting a phenotype rather than relying solely on an arbitrary scoring threshold for each individual gene. We employed Netwalk [28] here to facilitate identification of such gene sets based on overrepresentation of functionally coherent subnetworks within the graph (Figures S1, S2, S3, S4, S5, S6, S7, S8 and S9). One such subnetwork implicated prenylation of Rab-family GTPases in support of H1N1 replication ( Figure S4 and Figure 3D ). To test this we employed 3-IPEHPC, a specific inhibitor of the type II Geranylgeranyltransferases (IC50 of 1.27 mM and a K i of 0.211 mM for Rab1a modification [29] ). As such, 3-IPEHPC specifically inhibits modification of Rab-family proteins with a carboxy-terminal CC motif as opposed to the carboxy-terminal CAAX motif [29] . HBEC-30 cells pretreated with 3-IPEHPC for 24 hours were significantly refractory to infection by H1N1 (Figure 5A, B) . Inhibitory activity was observed at concentrations as low as 125 nM ( Figure 5C ). Unlike SB218078, A549 cells were also responsive to 3-IPEHPC ( Figure 5D, E) . While the use of a mouseadapted virus facilitates large-scale screening and allows comparisons with other published screening efforts, the extent to which results translate to seasonal or highly pathogenic strains is not established. Importantly, 3-IPEHPC was protective against infection with the avian strain H5/N1 and the recent pandemic swine flu strain H1/N1 ( Figure 5D, E) .