Type III phosphatidylinositol-4-kinase beta (PI4KIII␤) was previously implicated in hepatitis C virus (HCV) replication by small interfering RNA (siRNA) depletion and was therefore proposed as a novel cellular target for the treatment of hepatitis C. Medicinal chemistry efforts identified highly selective PI4KIII␤ inhibitors that potently inhibited the replication of genotype 1a and 1b HCV replicons and genotype 2a virus in vitro. Replicon cells required more than 5 weeks to reach low levels of 3-to 5-fold resistance, suggesting a high resistance barrier to these cellular targets. Extensive in vitro profiling of the compounds revealed a role of PI4KIII␤ in lymphocyte proliferation. Previously proposed functions of PI4KIII␤ in insulin secretion and the regulation of several ion channels were not perturbed with these inhibitors. Moreover, PI4KIII␤ inhibitors were not generally cytotoxic as demonstrated across hundreds of cell lines and primary cells. However, an unexpected antiproliferative effect in lymphocytes precluded their further development for the treatment of hepatitis C. C hronic hepatitis C virus (HCV) infection, a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma, afflicts approximately 3% of the world's population (24). The current standard of care for treating hepatitis C is pegylated interferon and ribavirin, which shows poor tolerability and is capable of achieving a sustained viral response in only half of genotype 1 patients (7). Two NS3 protease inhibitors, telaprevir and boceprevir, have been approved recently, and additional direct-acting antivirals are in clinical development. While triple therapy with interferon, ribavirin, and a protease inhibitor increases the percentage of patients showing a sustained viral response to 75% and can shorten the treatment time, it still has limitations: only genotype 1 patients are responsive, side effects (such as anemia) prevent the use in transplant patients, and the inconvenient dosing schedule (three times a day) might cause noncompliance. Development of viruses resistant to direct antivirals occurs very rapidly and leads to relapse and viral breakthrough. A possible exception might be nucleoside inhibitors, since viruses with resistance mutations are not viable. We therefore executed high-throughput small interfering RNA (siRNA) screens in order to identify novel cellular targets for the treatment of HCV. Type III phosphatidylinositol-4-kinases (PI4KIIIs) were identified from these studies and in screens performed in other laboratories (3,4,(20)(21)(22).Mammalian cells express a large number of lipid kinases, including four enzymes that phosphorylate phosphatidylinositol at position four of the inositol ring, the phosphatidylinositol-4-kinases (PI4Ks). Lipid kinases are involved in multiple functions of the cell, of which phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) signaling is the most thoroughly investigated process. The four PI4Ks (type II ␣ and ␤ and type III ␣ and ␤) are localized to different sites in the cell by pro...

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The development of methods aimed at polymorph screening and effecting phase control is of broad interest to the field of molecular materials. The present work is the most extensive systematic combinatorial study of molecular crystal growth in the presence of modified siloxane templates. 1,3-Bis(m-nitrophenyl)urea (MNPU) is known to crystallize from solution in three polymorphic forms (R, β, δ) as well as a hydrate (γ), typically concomitantly. Previous growth studies of MNPU on goldthiol self-assembled monolayers (SAMs) (J. Am. Chem. Soc. 2005, 127, 18321-18327) demonstrated phase selectivity and preferred orientations which could be rationalized on the basis of thermodynamic stabilization at the SAM/crystal interface. Crystallization studies of MNPU on 11 different siloxanes in 3 unique solvents showed that in general siloxane SAMs tended to favor the nucleation and growth of metastable phases (β, δ, γ) and completely suppress the growth of the most stable R phase. A new ε-MNPU phase not previously observed in either solution or template-directed studies was also identified. Differences in the preferred orientations and phase selectivity relative to Au-S SAMs growth studies suggest that kinetic factors play a more pronounced role during interfacial stabilization on siloxane SAMs. This method serves as an effective complement to existing strategies used in the discovery and reliable generation of polymorphs, and may have useful applications in the polymorph screening of other molecular crystal systems.

Hydrogen bonding between 1,3-bis ureas is a commonly used motif in the assembly of supramolecular structures such as gels, capsules and crystals. The title compound, 1,3-bis­(m-cyanophenyl)­urea (mCyPU), has previously been shown to crystallize in both an anhydrous and monohydrate phase (α and H–I). An expanded search for polymorphs and cocrystals of mCyPU revealed a much greater diversity of solid forms including three additional polymorphs (β, δ, ε), a second hydrate (H–II) and two cocrystal phases with dimethyl sulfoxide and triphenylphosphine oxide. Analysis of the single crystal structures obtained in this study shows that the typical 1-dimensional H-bonding between 1,3-bis urea groups is disrupted by the presence of other H-bond acceptors including cyano, water, sulfoxide and phosphine oxide functionalities. Re-examination of α-mCyPU additionally showed both blade and plate-like morphologies could be obtained from different growth solvents, with crystals of the latter morphology exhibiting a grain boundary migration prior to melting.

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