The NS5A replication complex inhibitor, BMS-790052, inhibits hepatitis C virus (HCV) replication with picomolar potency in preclinical assays. This potency translated in vivo to a substantial antiviral effect in a single-ascending dose study and a 14-day multiple-ascending dose (MAD) monotherapy study. However, HCV RNA remained detectable in genotype 1a-infected patients at the end of the MAD study. In contrast, viral breakthrough was observed less often in patients infected with genotype 1b, and, in several patients, HCV RNA declined and remained below the level of quantitation (<25 IU/mL) through the duration of treatment. Here, we report on the results of the genotypic and phenotypic analyses of resistant variants in 24 genotype 1-infected patients who received BMS-790052 (1, 10, 30, 60, and 100 mg, once-daily or 30 mg twice-daily) in the 14-day MAD study. Sequence analysis was performed on viral complementary DNA isolated from serum specimens collected at baseline and days 1 (4, 8, and 12 hours), 2, 4, 7, and 14 postdosing. Analyses of the sequence variants (1) established a correlation between resistant variants emerging in vivo with BMS-790052 treatment and those observed in the in vitro replicon system (major substitutions at residues 28, 30, 31, and 93 for genotype 1a and residues 31 and 93 for genotype 1b); (2) determined the prevalence of variants at baseline and the emergence of resistance at different times during dosing; and (3) revealed the resistance profile and replicative ability (i.e., fitness) of the variants. Conclusion: Although resistance emerged during monotherapy with BMS-790052, the substantial anti-HCV effect of this compound makes it an excellent candidate for effective combination therapy. (HEPATOLOGY 2011;54:1924-1935 T he hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a multifunctional protein with key roles in HCV replication. NS5A has also been implicated in the modulation of cellular signaling pathways. 1,2 Because it is required in vivo and in vitro for viral replication and has no known human homologs, NS5A provides an attractive target for therapeutic intervention. 3 BMS-790052 is a potent HCV NS5A replication complex inhibitor, with 50% effective concentration (EC 50 ) values of 9 and 50 pM against genotype 1b and 1a replicons, respectively. 4,5 It is also potent against live virus (genotype 2a, JFH-1), with an EC 50 of $28 pM. 4 BMS-790052 has broad genotype coverage, with EC 50 values ranging from pM to low nM for replicons with NS5A sequences derived from genotype 2a, 3a, 4a, and 5a. 4

With the fast development of organic electronics, organic semiconductors have been extensively studied for various optoelectronic applications, among which organic phototransistors recently emerged as one of the most promising light signal detectors. However, it is still a big challenge to endow organic phototransistors with both high mobility and high light-sensitivity because the low mobility of most organic photoresponsive materials limits the efficiency of transporting and collecting charge carriers. We herein report band-like charge transport in vacuum-deposited small-molecule thin films for organic phototransistor arrays which can be operated at very low dark currents (~10−12 A). Both high mobility and excellent optical figures of merit including photosensitivity, photoresponsivity and detectivity are achieved, wherein, unprecedentedly, a detectivity greater than 1017 cm Hz1/2 W−1 is obtained. All these key parameters are superior to state-of-the-art organic phototransistors, implying a great potential in optoelectronic applications.

Recent advances in photoswitchable molecular devices based on single molecules or self-assembled monolayers of photochromic molecules are summarized and discussed.

Phototransistors combine light detection and signal amplification functions into a single device and are regarded as one of the most important components for optoelectronic integration. In recent years, organic phototransistors (OPTs) have attracted worldwide interest because of their potential advantages of low cost, light weight, excellent flexibility and broadband detection. In this review, a brief description of the working mechanisms and performance metrics of OPTs is presented. Afterwards, the recent progress of OPTs based on the conventional planar fieldeffect transistor structure is presented. Furthermore, from the perspective of novel device architectures and interface engineering, strategies for improving the performance of OPTs are discussed. Flexible optoelectronic devices based on OPTs for potential application in next-generation wearable and humanfriendly electronics are also highlighted. Finally, an outlook for future research directions and challenges for OPTs is provided.

BMS-790052, a first-in-class hepatitis C virus (HCV) replication complex inhibitor, targeting nonstructural protein 5A (NS5A), displays picomolar to nanomolar potency against genotypes 1 to 5. This exceptional potency translated into robust anti-HCV activity in clinical studies with HCV genotype 1-infected subjects. To date, all BMS-790052-associated resistance mutations have mapped to the N-terminal region of NS5A. To further characterize the antiviral activity of BMS-790052, HCV replicon elimination and colony formation assays were performed. Replicon was cleared from genotype 1a and 1b replicon cells in a time-and dose-dependent manner. Elimination of the genotype 1a replicon required longer treatment durations and higher concentrations of BMS-790052 than those for the genotype1b replicon. Single amino acid substitutions that conferred relatively low levels of resistance were observed at early time points and at low doses. Higher doses and longer treatment durations yielded mutations that conferred greater levels of resistance, including linked amino acid substitutions. Replicon cells that survived inhibitor treatment remained fully sensitivity to pegylated alpha interferon (pegIFN-␣) and other HCV inhibitors. Moreover, genotype 1a replicon elimination was markedly enhanced when pegIFN-␣ and BMS-790052 were combined. Resistant variants observed in this study were very similar to those observed in a multiple ascending dose (MAD) monotherapy trial of BMS-790052, validating replicon elimination studies as a model to predict clinical resistance. Insights gained from the in vitro anti-HCV activity and resistance profiles of BMS-790052 will be used to help guide the clinical development of this novel HCV inhibitor. H epatitis C virus (HCV), a member of the Flaviviridae family of RNA viruses, is a major cause of liver disease worldwide (1). The ϳ9.6-kb HCV genome encodes a polyprotein that is processed into structural proteins (core, E1, and E2), a small ion channel protein (p7), and nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) required for polyprotein processing and RNA replication (2). Until very recently, standard-of-care therapy for HCV-infected individuals consisted of a combination of pegylated interferon (pegIFN) and ribavirin (RBV) (18). Because of complications with side effects and incomplete antiviral efficacy, only ϳ50% of individuals infected with HCV genotype 1 achieved a sustained viral response upon treatment (18). Today, an increasing number of small-molecule inhibitors targeting specific viral proteins are in various stages of development, and two drugs that target the HCV NS3 protease, telaprevir and boceprevir, have been approved for clinical use for HCV genotype 1-infected patient treatment in combination with pegIFN and RBV. Collectively referred to as directly acting antiviral agents (DAA), these virus-specific inhibitors hold the promise of improving or even replacing IFN-based HCV therapy (9). Many of the DAA in development are directed against the viral enzymatic activities...