A survey of core replacements in indole-based HIV-1 attachment inhibitors.

Indole- and azaindole-based glyoxylyl amide derivatives have been described as HIV-1 attachment inhibitors (AIs) that act by blocking the interaction between the viral gp120 coat protein and the human host cell CD4 receptor. As part of an effort to more deeply understand the role of the indole/azaindole heterocycle in the expression of antiviral activity, a survey of potential replacements was conducted using parallel synthesis methodology. The design and optimization was guided by a simple 2-dimensional overlay based on an overall planar topography between the indole/azaindole and C-7 substituents that had been deduced from structure-activity studies leading to the discovery of temsavir (3). 2-Substituted naphthalene- and quinoline-derived chemotypes emerged as the most interesting prototypes, with C-5 and C-6 substituents enhancing antiviral potency. Despite the fact that neither of these chemotypes incorporated a H-bond donor that has been shown to engage the side chain carboxylate of Asp113 in gp120, the antiviral potency of several analogues met or exceeded that of 3, demonstrating that engaging Asp113 is not a prerequisite for potent antiviral activity.

Ferrocene-based inhibitors of hepatitis C virus replication that target NS5A with low picomolar in vitro antiviral activity.

An unprecedented series of organometallic HCV (hepatitis C virus) NS5A (nonstructural 5A protein) replication complex inhibitors that incorporates a 1,1'-ferrocenediyl scaffold was explored. This scaffold introduces the elements of linear flexibility and non-planar topology that are unconventional for this class of inhibitors. Data from 2-D NMR spectroscopic analyses of these complexes in solution support an anti (unstacked) arrangement of the pharmacophoric groups. Several complexes demonstrate single-digit picomolar in vitro activity in an HCV genotype-1b replicon system. One complex to arise from this investigation (10a) exhibits exceptional picomolar activity against HCV genotype 1a and 1b replicons, low hepatocellular cytotoxicity, and good pharmacokinetic properties in rat.

Synthesis, microstructural and optical characterizations of sol-gel grown gadolinium doped cerium oxide ceramics.

In this study, through the utilization of the sol-gel combustion tactic, gadolinium (Gd)-doped cerium oxide (CeO2), Ce1-xGdxO2 (x = 0.00, 0.10, 0.20 and 0.30 (GDC)) ceramics were attained. The synthesized GDC ceramics were investigated using X-ray diffraction (XRD) to scrutinize their crystal structures and phase clarities. The obtained GDC ceramics have a single-phase cubic structure and belong to the crystallographic space group fm3̄m (225). The measurement of the diffraction angle of each reflection and the subsequent smearing of the renowned Bragg's relation provided coarse d-interplanar spacings. The stacking fault (SF) values of pure and Gd-doped CeO2 ceramics were assessed. To muse the degree of preferred orientation (σ) of crystallites along a crystal plane (h k l), the texture coefficient (Ci) of each XRD peak of GDC ceramics is gauged. By determining the interplanar distance (dh k l), the Bravais theory sheds light on the material's development. By exploiting Miller indices for the prime (1 1 1) plane, the lattice constants of GDC ceramics and cell volumes were obtained. Multiple techniques were employed to ascertain the microstructural parameters of GDC ceramics. A pyrometer substantiated the density of GDC ceramics. The room temperature (RT) Fourier transform infrared (FTIR) spectra of both un-doped and Gd-doped CeO2 were obtained. The UV-vis-NIR spectrometer recorded the GDC ceramics' reflectance (R) spectra at RT. For both undoped and Gd-doped CeO2, the absorption coefficient (α) spectra showed two distinct peaks. The R-dependent refractive index (η) and the α-dependent extinction coefficient (k) were determined for all GDC samples. The optical band gap (Eg) was obtained by integrating the Tauc and Kubelka-Munk approaches for GDC ceramics. For each GDC sample, the imaginary (εi) and real (εr) dielectric constants, as well as the dissipation factor (tan δ), were determined local to the characteristic wavelength (λc). Calculations were made for the Urbach energy (EU) and Urbach absorption coefficient (α0) for GDC ceramics. The minimum and maximum values of optical (σo) and electrical (σe) conductivity for GDC ceramics were determined. The volume (VELF) and surface (SELF) energy loss functions, which depend on the constants εi and εr, were used to measure electrons' energy loss rates as they travel across the surface. Raman spectroscopy revealed various vibrational modes in GDC ceramics. Finally, the implications are discussed herein.

ACH-806, an NS4A antagonist, inhibits hepatitis C virus replication by altering the composition of viral replication complexes.

Treatment of hepatitis C patients with direct-acting antiviral drugs involves the combination of multiple small-molecule inhibitors of distinctive mechanisms of action. ACH-806 (or GS-9132) is a novel, small-molecule inhibitor specific for hepatitis C virus (HCV). It inhibits viral RNA replication in HCV replicon cells and was active in genotype 1 HCV-infected patients in a proof-of-concept clinical trial (1). Here, we describe a potential mechanism of action (MoA) wherein ACH-806 alters viral replication complex (RC) composition and function. We found that ACH-806 did not affect HCV polyprotein translation and processing, the early events of the formation of HCV RC. Instead, ACH-806 triggered the formation of a homodimeric form of NS4A with a size of 14 kDa (p14) both in replicon cells and in Huh-7 cells where NS4A was expressed alone. p14 production was negatively regulated by NS3, and its appearance in turn was associated with reductions in NS3 and, especially, NS4A content in RCs due to their accelerated degradation. A previously described resistance substitution near the N terminus of NS3, where NS3 interacts with NS4A, attenuated the reduction of NS3 and NS4A conferred by ACH-806 treatment. Taken together, we show that the compositional changes in viral RCs are associated with the antiviral activity of ACH-806. Small molecules, including ACH-806, with this novel MoA hold promise for further development and provide unique tools for clarifying the functions of NS4A in HCV replication.

Pristine, Ni- and Zn-Doped CuSe Nanoparticles: An Antimicrobial, Antioxidant, and Cytotoxicity Study.

The strategy of chemical coprecipitation is implemented to synthesize nanoparticles of pristine CuSe, 5 and 10% Ni-doped CuSe, and 5 and 10% Zn-doped CuSe. All of the nanoparticles are found to be near stoichiometric by the evaluation of X-ray energy using electron dispersion spectra, and the elemental mapping shows uniform distribution. By X-ray diffraction examination, all of the nanoparticles are identified as being single-phase and having a hexagonal lattice structure. Field emission microscopy with electrons in both scanning and transmission modes affirmed the spherical configuration of the nanoparticles. The crystalline nature of the nanoparticles is confirmed by the presence of spot patterns observed in the selected area electron diffraction patterns. The observed d value matches well with the d value of the CuSe hexagonal (102) plane. Findings from dynamic light scattering reveal the size distribution of nanoparticles. The nanoparticle's stability is investigated by ζ potential measurements. Pristine and Ni-doped CuSe nanoparticles exhibit ζ potential values in the preliminary stability band of ±10 to ±30 mV, while Zn-doped nanoparticles feature moderate stability levels of ±30 to ±40 mV. The potent antimicrobial effects of synthesized nanoparticles are studied against Staphylococcus aureus, Pseudomonas aeruginosa, Proteus vulgaris, Enterobacter aerogenes, and Escherichia coli bacteria. The 2,2-diphenyl-1-picrylhydrazyl scavenging test is used to investigate the nanoparticle's antioxidant activities. The results showed the highest activity for control (Vitamin C) with an IC50 value of 43.6 µg/mL, while the lowest for Ni-doped CuSe nanoparticles with an IC50 value of 106.2 µg/mL. Brine shrimps are utilized for in vivo cytotoxicity evaluation of the synthesized nanoparticles, which demonstrates that 10% Ni- and 10% Zn-doped CuSe nanoparticles are more damaging on brine shrimp instead on other nanoparticles with a 100% mortality rate. The lung cancer cell line of human (A549) is used to investigate in vitro cytotoxicity. The results indicate that pristine CuSe nanoparticles are more effective in the context of cytotoxicity against the A549 cell lines, possessing an IC50 of 488 µg/mL. The particulars of the outcomes are explained in depth.

In vitro and in vivo profiles of ACH-702, an isothiazoloquinolone, against bacterial pathogens.

ACH-702, a novel isothiazoloquinolone (ITQ), was assessed for antibacterial activity against a panel of Gram-positive and Gram-negative clinical isolates and found to possess broad-spectrum activity, especially against antibiotic-resistant Gram-positive strains, including methicillin-resistant Staphylococcus aureus (MRSA). For Gram-negative bacteria, ACH-702 showed exceptional potency against Haemophilus influenzae, Moraxella catarrhalis, and a Neisseria sp. but was less active against members of the Enterobacteriaceae. Good antibacterial activity was also evident against several anaerobes as well as Legionella pneumophila and Mycoplasma pneumoniae. Excellent bactericidal activity was observed for ACH-702 against several bacterial pathogens in time-kill assays, and postantibiotic effects (PAEs) of >1 h were evident with both laboratory and clinical strains of staphylococci at 10 × MIC and similar in most cases to those observed for moxifloxacin at the same MIC multiple. In vivo efficacy was demonstrated against S. aureus with murine sepsis and thigh infection models, with decreases in the number of CFU/thigh equal to or greater than those observed after vancomycin treatment. Macromolecular synthesis assays showed specific dose-dependent inhibition of DNA replication in staphylococci, and biochemical analyses indicated potent dual inhibition of two essential DNA replication enzymes: DNA gyrase and topoisomerase IV. Additional biological data in support of an effective dual targeting mechanism of action include the following: low MIC values (≤0.25 µg/ml) against staphylococcal strains with single mutations in both gyrA and grlA (parC), retention of good antibacterial activity (MICs of ≤0.5 µg/ml) against staphylococcal strains with two mutations in both gyrA and grlA, and low frequencies for the selection of higher-level resistance (<10⁻¹°). These promising initial data support further study of isothiazoloquinolones as potential clinical candidates.

Identification of hepatitis C virus NS5A inhibitors.

Using a cell-based replicon screen, we identified a class of compounds with a thiazolidinone core structure as inhibitors of hepatitis C virus (HCV) replication. The concentration of one such compound, BMS-824, that resulted in a 50% inhibition of HCV replicon replication was approximately 5 nM, with a therapeutic index of >10,000. The compound showed good specificity for HCV, as it was not active against several other RNA and DNA viruses. Replicon cells resistant to BMS-824 were isolated, and mutations were identified. A combination of amino acid substitutions of leucine to valine at residue 31 (L31V) and glutamine to leucine at residue 54 (Q54L) in NS5A conferred resistance to this chemotype, as did a single substitution of tyrosine to histidine at amino acid 93 (Y93H) in NS5A. To further explore the region(s) of NS5A involved in inhibitor sensitivity, genotype-specific NS5A inhibitors were used to evaluate a series of genotype 1a/1b hybrid replicons. Our results showed that, consistent with resistance mapping, the inhibitor sensitivity domain also mapped to the N terminus of NS5A, but it could be distinguished from the key resistance sites. In addition, we demonstrated that NS5A inhibitors, as well as an active-site inhibitor that specifically binds NS3 protease, could block the hyperphosphorylation of NS5A, which is believed to play an essential role in the viral life cycle. Clinical proof of concept has recently been achieved with derivatives of these NS5A inhibitors, indicating that small molecules targeting a nontraditional viral protein like NS5A, without any known enzymatic activity, can also have profound antiviral effects on HCV-infected subjects.

Biocompatible CuInS2 Nanoparticles as Potential Antimicrobial, Antioxidant, and Cytotoxic Agents.

A simple hydrothermal route is employed to synthesize pure copper indium disulfide (CIS) and CIS nanoparticles (NPs) mediated by various natural plant extracts. The plant extracts used to mediate are Azadirachta indica (neem), Ocimum sanctum (basil), Cocos nucifera (coconut), Aloe vera (aloe), and Curcuma longa (turmeric). The tetragonal unit cell structure of as-synthesized NPs is confirmed by X-ray diffraction. The analysis by energy-dispersive X-rays shows that all the samples are near-stoichiometric. The morphologies of the NPs are confirmed by high-resolution scanning and transmission modes of electron microscopy. The thermal stability of the synthesized NPs is determined by thermogravimetric analysis. The optical energy band gap is determined from the absorption spectra using Tauc's equation. The antimicrobial activity analysis and the estimation of the minimum inhibitory concentration (MIC) value of the samples are performed for Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Enterobacter aerogenes, and Staphylococcus aureus pathogens. It shows that the aloe-mediated CIS NPs possess a broad inhibitory spectrum. The best inhibitory effect is observed against S. aureus, whereas the least effect was exhibited against P. vulgaris. The least MIC value is found for aloe-mediated CIS NPs (0.300 mg/mL) against S. aureus, P. aeruginosa, and E. aerogenes, along with basil-mediated NPs against E. coli. The antioxidant activity study showed that the IC50 value to inhibit the scavenging activity is maximum for the control (vitamin C) and minimum for pure CIS NPs. The in vivo cytotoxicity study using brine shrimp eggs shows that the pure CIS NPs are more lethal to brine shrimp than the natural extract-mediated CIS NPs. The in vitro cytotoxicity study using the human lung carcinoma cell line (A549) shows that the IC50 value of turmeric extract-mediated CIS NPs is minimum (15.62 ± 1.58 µg/mL). This observation reveals that turmeric extract-mediated CIS NPs are the most potent in terms of cytotoxicity toward the A549 cell line.

Inhibitors of HIV-1 attachment. Part 3: A preliminary survey of the effect of structural variation of the benzamide moiety on antiviral activity.

1-(4-Benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1a) has been characterized as an inhibitor of HIV-1 attachment that interferes with the interaction of viral gp120 with the host cell receptor CD4. In previous studies, the effect of indole substitution pattern on antiviral activity was probed. In this Letter, the effect of structural variation of the benzamide moiety is described, a study that reveals the potential or the phenyl moiety to be replaced by five-membered heterocyclic rings and a restricted tolerance for the introduction of substituents to the phenyl ring.

Inhibitors of HIV-1 attachment. Part 2: An initial survey of indole substitution patterns.

The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype. Small alkyl substituents at N-1 exerted minimal effect on activity whilst increasing the size of the alkyl moiety led to progressively reduced inhibitory properties. These studies establish a basic understanding of the indole element of the HIV attachment inhibitor pharmacophore.

Selection of replicon variants resistant to ACH-806, a novel hepatitis C virus inhibitor with no cross-resistance to NS3 protease and NS5B polymerase inhibitors.

We have discovered a novel class of compounds active against hepatitis C virus (HCV), using a surrogate cellular system, HCV replicon cells. The leading compound in the series, ACH-806 (GS-9132), is a potent and specific inhibitor of HCV. The selection of resistance replicon variants against ACH-806 was performed to map the mutations conferring resistance to ACH-806 and to determine cross-resistance profiles with other classes of HCV inhibitors. Several clones emerged after the addition of ACH-806 to HCV replicon cells at frequencies and durations similar to that observed with NS3 protease inhibitors and NS5B polymerase inhibitors. Phenotypic analyses of these clones revealed that they are resistant to ACH-806 but remain sensitive to other classes of HCV inhibitors. Moreover, no significant change in the susceptibility to ACH-806 was found when the replicon cellular clones resistant to NS3 protease inhibitors and NS5B polymerase inhibitors were examined. Sequencing of the entire coding region of ACH-806-resistant replicon variants yielded several consensus mutations. Reverse genetics identified two single mutations in NS3, a cysteine-to-serine mutation at amino acid 16 and an alanine-to-valine mutation at amino acid 39, that are responsible for the resistance of the replicon variants to ACH-806. Both mutations are located at the N terminus of NS3 where extensive interactions with the central hydrophobic region of NS4A exist. These data provide evidence that ACH-806 inhibits HCV replication by a novel mechanism.

A highly sensitive and reproducible HCV RNA hybridization method valuable for antiviral drug discovery.

Real-time RT-PCR and Northern blot are employed for the measurement of HCV RNA but suffer from multiple purification steps, high cost, and relatively large variability. In this study, a hybridization method for HCV RNA detection is described. This method does not need RNA purification, and is sensitive enough to detect HCV RNA present in replicon cellular lysates harvested from a single well of a 96-well plate. Fixation of RNA by UV cross-linking is crucial for this sensitivity. A linear relationship exists between hybridization signal and cell density ranging from 10(5) to as few as 300 cells per well. The signal-to-background ratio is greater than 40 and the Z factor is above 0.7. Using several known anti-HCV agents, dose-response curves and EC(50) values generated from hybridization were similar to those obtained from a luciferase assay. This method has been successfully applied to replicons of different HCV subtypes and hepatitis B virus in our laboratory. In summary, this hybridization assay is sensitive, highly reproducible, easy to handle, and a valuable tool for antiviral drug discovery.

Isothiazoloquinolones with enhanced antistaphylococcal activities against multidrug-resistant strains: effects of structural modifications at the 6-, 7-, and 8-positions.

We describe the biological evaluation of isothiazoloquinolones (ITQs) having structural modifications at the 6-, 7-, and 8-positions. Addition of a methoxy substituent to C-8 effected an increase in antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and a decrease in cytotoxic activity against Hep2 cells. Removal of fluorine from C-6 or replacement of the C-8 carbon with a nitrogen compromised anti-MRSA activity. When the groups attached at C-7 were compared, the anti-MRSA activity decreased in the order 6-isoquinolinyl > 4-pyridinyl > 5-dihydroisoindolyl > 6-tetrahydroisoquinolinyl. The compound with the most desirable in vitro biological profile was 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione (7g). This ITQ demonstrated (i) strong in vitro anti-MRSA activity (MIC90 = 0.5 microg/mL), (ii) strong inhibitory activities against S. aureus DNA gyrase and topoisomerase IV, with weak activity against human topoisomerase II, (iii) weak cytotoxic activities against three cell lines, and (iv) efficacy in an in vivo murine thigh model of infection employing MRSA.

Multiple Carpometacarpal Dislocations of the Hand - An Uncommon Variant: A Rare Case.

Carpometacarpal fracture dislocations of the hand are a relatively uncommon injury. The injury is difficult to diagnose because of the gross swelling of the hand. The diagnosis of this unusual form of injury requires a high index of suspicion, vigilant examination and high-quality radiography. This article reports a case of young male grieved with dislocation of all carpometacarpal (CMC) joints due to motor vehicle collision. Standard radiographs and CT scan revealed dorsal dislocations of second to fourth CMC joints, volar fracture dislocation of fifth carpometacarpal joint, fracture dislocation of CMC joint of thumb and dorsal dislocation of the trapezoid. Patient was treated with closed manipulation and percutaneous pinning with multiple K - wires. Follow up radiographs showed adequate reduction and fracture union. Intensive postoperative physiotherapy is vital for achieving a good outcome.

Isothiazolopyridones: synthesis, structure, and biological activity of a new class of antibacterial agents.

We report the syntheses of first-generation derivatives of isothiazolopyridones and their in vitro evaluation as antibacterial agents. These compounds, containing a novel heterocyclic nucleus composed of an isothiazolone fused to a quinolizin-4-one (at C-2 and C-3 of the quinolizin-4-one), were prepared using a sequence of seven synthetic transformations. The solid-state structure of 7-chloro-9-ethyl-1-thia-2,4a-diazacyclopenta[b]naphthalene-3,4-dione was determined by X-ray diffraction. The prepared derivatives of desfluoroisothiazolopyridones exhibited (a) antibacterial activity against Gram-negative and Gram-positive organisms, (b) inhibitory activities against DNA gyrase and topoisomerase IV, and (c) no inhibitory activity against human topoisomerase II.

Zinc Oxide Nanoparticles Supported Lipase Immobilization for Biotransformation in Organic Solvents: A Facile Synthesis of Geranyl Acetate, Effect of Operative Variables and Kinetic Study.

The present study describes grafting of zinc oxide (ZnO) nanoparticles with polyethyleneimine (PEI) followed by modification with glutraldehyde used as the bridge for binding the enzyme to support. The prepared nanocomposites were then characterized using Fourier transform infrared spectroscopy, thermogravimetric analysis, and transmission electron microscopy, utilized for synthesis of geranyl acetate in n-hexane. Among all the three prepared nanocomposites (ZnO + PEI, ZnO + PEI + SAA, ZnO + PEI + GLU), Candida rugosa lipase immobilized on ZnO-PEI-GLU was found to be best for higher ester synthesis. The operating conditions that maximized geranyl acetate resulted in the highest yield of 94 % in 6 h, molar ratio of 0.1:0.4 M (geraniol/vinyl acetate) in the presence of n-hexane as reaction medium. Various kinetic parameters such as V max, K i(G), K m(G), and K m(VA) were determined using nonlinear regression analysis for order bi-bi mechanism. The kinetic study showed that reaction followed order bi-bi mechanism with inhibition by geraniol. Activation energy (E a ) was found to be lower for immobilized lipase (12.31 kJ mol(-1)) than crude lipase (19.04 kJ mol(-1)) indicating better catalytic efficiency of immobilized lipase. Immobilized biocatalyst demonstrated 2.23-fold increased catalytic activity than crude lipase and recycled 20 times. The studies revealed in this work showed a promising perspective of using low-cost nanobiocatalysts to overcome the well-known drawbacks of the chemical-catalyzed route.

Whale's tail technique: A case series.

The Whale's tail technique performed to obtain maximum interdental papilla fill in the anterior region after placement of bone grafts. This study aims to assess the clinical efficacy of this new technique. This report describes a series of three cases with a probing depth of 6-7 mm in the maxillary anterior teeth and their treatment with Whale's tail technique to obtain regeneration and maximum papilla preservation. The cases in this report showed a pocket depth reduction of 3-4mm and a clinical attachment gain of 3-4mm. The application of the "Whale's tail" flap leads to clinically significant improvement of hard and soft tissue conditions and allows regeneration of wide intrabony defects involving the maxillary anterior teeth with notable interdental diastemas, maintaining interproximal tissue to recreate a functional attachment with esthetic results.

Design and synthesis of a fluoroindolocarbazole series as selective topoisomerase I active agents. Discovery of water-soluble 3,9-difluoro-12,13-dihydro-13-[6-amino-beta-D-glucopyranosyl]-5H,13H-benzo[b]- thienyl[2,3-a]pyrrolo[3,4-c]carbazole- 5,7(6H)-dione (BMS-251873) with curative antitumor activity against prostate carcinoma xenograft tumor model.

A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.

Discovery of 4-benzoyl-1-[(4-methoxy-1H- pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2- (R)-methylpiperazine (BMS-378806): a novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions.

Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.

Hepatitis C drug discovery: in vitro and in vivo systems and drugs in the pipeline.

The combination therapy of ribavirin and pegylated interferon-alpha for hepatitis C has significant side effects, is often poorly tolerated and is ineffective in many patients, despite causing impressive improvement in the sustained virological response. Discovery and development of more effective and well-tolerated antihepatitis C virus drugs are clearly in great demand. During the past few years, remarkable advances have been made in the establishment of in vitro and in vivo systems. Armed with these systems, a wave of specific antihepatitis C virus compounds have been discovered and are moving into the clinical phase. More effective combination therapies with specific antivirals are predicted to emerge in the near future for the treatment of hepatitis C.