共查询到8条相似文献,搜索用时 0 毫秒
1.
Jose Ignacio Martin Hernando Dr. Jesus Maria Ontoria Dr. Savina Malancona Barbara Attenni Fabrizio Fiore Fabio Bonelli Uwe Koch Dr. Stefania Di Marco Dr. Stefania Colarusso Simona Ponzi Nadia Gennari Sue Ellen Vignetti Maria del Rosario Rico Ferreira Dr. Jörg Habermann Dr. Michael Rowley Dr. Frank Narjes Dr. 《ChemMedChem》2009,4(10):1695-1713
Infections caused by the hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The NS5B polymerase of HCV is responsible for the replication of viral RNA and has been a prime target in the search for novel treatment options. We had discovered allosteric finger‐loop inhibitors based on a thieno[3,2‐b]pyrrole scaffold as an alternative to the related indole inhibitors. Optimization of the thienopyrrole series led to several N‐acetamides with submicromolar potency in the cell‐based replicon assay, but they lacked oral bioavailability in rats. By linking the N4‐position to the ortho‐position of the C5‐aryl group, we were able to identify the tetracyclic thienopyrrole 40 , which displayed a favorable pharmacokinetic profile in rats and dogs and is equipotent with recently disclosed finger‐loop inhibitors based on an indole scaffold. 相似文献
2.
Analysis of Structure–Activity Relationships Based on the Hepatitis C Virus SLIIb Internal Ribosomal Entry Sequence RNA‐Targeting GGHYRFK⋅Cu Complex
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Martin James Ross Insiya Fidai Dr. James A. Cowan 《Chembiochem : a European journal of chemical biology》2017,18(17):1743-1754
New therapeutics for targeting the hepatitis C virus (HCV) have been released in recent years. Although they are less prone to resistance, they are still administered in cocktails as a combination of drugs targeting various aspects of the viral life cycle. Herein, we aim to contribute to an arsenal of new HCV therapeutics by targeting the HCV internal ribosomal entry sequence (IRES) RNA through the development of catalytic metallodrugs that function to degrade rather than inhibit the target molecule. Based on a previously characterized HCV IRES stem‐loop IIb RNA‐targeting metallopeptide Cu‐GGHYrFK ( 1? Cu), an all‐l analogue ( 3? Cu) and a series of additional complexes with single alanine substitutions in the targeting domain were prepared and screened to determine the influence each amino acid side chain on RNA localization and recognition, and catalytic reactivity toward the RNA. Additional substitutions of the tyrosine position in complex 3? Cu were also investigated. Good agreement between calculated and measured binding affinities provided support for in silico modeling of the SLIIb RNA binding site and correlations with RNA cleavage sites. Examination of the cleavage products from reaction of the Cu complexes with SLIIb provided mechanistic insights, with the first observation of the 5′‐geminal diol and 5′‐phosphopropenal as products through the use of a Cu ? ATCUN catalytic motif. Together, the data yielded insights into structure–function relationships that will guide future optimization efforts. 相似文献
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Dynamics of the Intrinsically Disordered C‐Terminal Domain of the Nipah Virus Nucleoprotein and Interaction with the X Domain of the Phosphoprotein as Unveiled by NMR Spectroscopy
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Lorenzo Baronti Dr. Jenny Erales Dr. Johnny Habchi Prof. Isabella C. Felli Prof. Roberta Pierattelli Dr. Sonia Longhi 《Chembiochem : a European journal of chemical biology》2015,16(2):268-276
5.
The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile—Part 2
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Florian Wakenhut Thien Duc Tran Dr. Chris Pickford Stephen Shaw Dr. Mike Westby Caroline Smith‐Burchnell Lesa Watson Michael Paradowski Dr. Jared Milbank David Stonehouse Dr. Kathy Cheung Dr. Robert Wybrow Dr. Felice Daverio Dr. Samuel Crook Keith Statham Dr. David Leese Dr. Darren Stead Fiona Adam Duncan Hay Dr. Lee R. Roberts Jean‐Yves Chiva Carly Nichols Dr. David C. Blakemore Gilles H. Goetz Dr. Ye Che Iain Gardner Satish Dayal Dr. Andrew Pike Rob Webster Dr. David C. Pryde 《ChemMedChem》2014,9(7):1387-1396
In ongoing studies towards novel hepatitis C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl‐linked pyrrolidine NS5A replication complex inhibitors were probed and structure–activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H‐bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second‐generation antiviral agents targeting NS5A. 相似文献
6.
The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile—Part 1
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Thien Duc Tran Florian Wakenhut Dr. Chris Pickford Stephen Shaw Dr. Mike Westby Caroline Smith‐Burchnell Lesa Watson Michael Paradowski Dr. Jared Milbank Dr. Rebecca A. Brimage Rebecca Halstead Dr. Rebecca Glen Dr. Craig P. Wilson Fiona Adam Duncan Hay Jean‐Yves Chiva Carly Nichols Dr. David C. Blakemore Iain Gardner Satish Dayal Dr. Andrew Pike Rob Webster Dr. David C. Pryde 《ChemMedChem》2014,9(7):1378-1386
Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol–Myers–Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl‐imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)‐1‐((S)‐2‐(4‐(4‐(6‐(2‐((S)‐1‐((methoxycarbonyl)‐L ‐valyl)pyrrolidin‐2‐yl)‐1H‐imidazol‐5‐yl)quinoxalin‐2‐yl)phenyl)‐1H‐imidazol‐2‐yl)pyrrolidin‐1‐yl)‐3‐methyl‐1‐oxobutan‐2‐yl)carbamate ( 17 ), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half‐life. This compound represents a promising lead that warrants further evaluation. 相似文献
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The results of a study of the relation between the oriented structure and drawn Poly(ε‐caprolactone) specimens including CaCO3 particles and their dynamic mechanical properties are presented. The loss elasticity, E″, showed almost the same curve for both undrawn sheets and drawn sheets as a function of CaCO3 content. On the other hand, the storage modulus, E′, of drawn sheets increased nonlinearly with increasing CaCO3 content, and their curve showed lower E′ values than those of undrawn sheets. By simulation of 13C CP NMR spectra of drawn PCL/CaCO3 sheets, both oriented and unoriented components were observed. The distribution parameter, p, of drawn PCL/CaCO3 sheets was 13°, which was larger than those (8°) of drawn PCL. Further, the fraction of the unoriented component increased with increasing CaCO3 content. Thus, adding CaCO3 particles into the PCL, the arrangement of the oriented component was disturbed and decreased. In addition, from the line shape analyses of 13C CP MAS NMR spectra, four peaks were obtained in not only undrawn sheets but also in drawn sheets of both PCL and PCL/CaCO3 compounds. Besides, structural change occurred at only drawn PCL/CaCO3 sheets. Therefore, the change in dynamic mechanical properties observed only for drawn PCL/CaCO3 sheets were strongly dependent on the orientational structure, which was formed under shear stress of the stretching drawn process. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 80: 2376–2382, 2001 相似文献
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In this study, a series of aliphatic–aromatic poly(butylene terephthalate‐co‐ε‐caprolactone) (PBTCL) copolyesters were synthesized from various monomeric compositions of terephthalic acid (TPA), 1,4‐butanediol (BDO), and ε‐caprolactone (CL) in the presence of tetrabutyl titanate (Ti(Obu)4) and stannous octoate (Sn(Oct)2) as catalysts through a combination of polycondensation and ring opening polymerization. A significant increase in the melting temperature (Tm) of copolyesters was observed by increasing the TPA/(CL+TPA) molar ratio, starting from the low end (Tm 66.2°C) of pure poly‐ε‐caprolactone PCL upward. We found that PBTCL‐50, which has a TPA/(CL+TPA) 50% molar ratio and polycondensation at 260°C for 1.5 h, resulted in a proper Tm of 139.2°C that facilitates thermal extrusion from biomass or other biodegradable polymers of similar Tm. The number–average molecular weight (Mn) of 7.4 × 104 for PBTCL‐50 was determined from the intrinsic viscosity [η] by using the Berkowitz model of Mn = 1.66 × 105[η]0.9. Good mechanical properties of PBTCL‐50 have been shown by tensile stretching experiment that indicates tensile strength, elongation, and Young's modulus are 11.9 MPa, 132%, and 257 MPa, respectively. Polymers with aforementioned properties are suitable for manufacturing biodegradable plastic films for downstream agricultural applications or merely for trash bag. This article reveals that the PBTCL‐50 contains all five monomers with different molar ratios and characteristical linkages between each other. The novel structure was furthermore analyzed by 1H‐ and 13C‐NMR spectroscopy. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013 相似文献