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2.
Aliment Pharmacol Ther ; 59 Suppl 1: S10-S22, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38451123

RESUMEN

BACKGROUND: Insulin resistance and lipotoxicity are extremely interconnected but fundamental in setting the stage for the development of MASLD/MASH. AIM/METHODS: A comprehensive literature search was performed and key themes were synthesised to provide insight into the underlying molecular mechanisms of insulin resistance and lipotoxicity in the liver, muscle, pancreas and adipose tissue and how organ cross-talk is fundamental to driving disease pathogenesis. RESULTS: Classical thinking postulates that excess FFA load exceeds the storage capacity of adipose tissue, which is predicated upon both genetic and environmental factors. This results in insulin resistance and compensatory hyperinsulinaemia by pancreatic beta cells to overcome target organ insulin resistance. As adipocyte dysfunction worsens, not only are excess FFA delivered to other organs, including skeletal muscle, pancreas and liver but a pro-inflammatory milieu is established with increases in IL-6, TNF-α and changes in adipokine levels (increased leptin and decreased adiponectin). With increased intramuscular lipid accumulation, lipotoxic species decrease insulin signalling, reduce glucose uptake by downregulation of GLUT4 and decrease glycogen synthesis. With this additional reduced capacity, hyperglycaemia is further exacerbated and increased FFA are delivered to the liver. The liver has the largest capacity to oxidise fat and to adapt to these stressors and, therefore, has become the last line of defence for excess lipid storage and utilisation, the capacity of which may be impacted by genetic and environmental factors. However, when the liver can no longer keep up with increasing FFA delivery and DNL, lipotoxic species accumulate with ensuing mitochondrial dysfunction, increased ER stress, oxidant stress and inflammasome activation, all of which drive hepatocyte injury and apoptosis. The resulting wound healing response, marked by stellate cell activation, drives collagen accumulation, progressive fibrosis, and, ultimately, end organ failure and death. This vicious cycle and complex interplay between insulin resistance, hyperinsulinaemia, lipotoxicity and multi-directional cross-talk among different target organs are critical drivers of MASLD/MASH. CONCLUSIONS: Targeting tissue-specific insulin resistance and hyperinsulinaemia while decreasing FFA load (lipotoxicity) through dietary and lifestyle changes remain the best upstream interventions.


Asunto(s)
Resistencia a la Insulina , Humanos , Resistencia a la Insulina/fisiología , Tejido Adiposo/metabolismo , Metabolismo de los Lípidos/fisiología , Músculo Esquelético/metabolismo , Hígado/metabolismo
3.
BMJ Open Qual ; 12(Suppl 3)2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37863507

RESUMEN

The rising trend in caesarean section (CS) rate is a global concern and, in this hospital too, it rose from 21.5% in 2010 to 32.6% in 2018. The team followed the point of care quality improvement methodology and conducted a series of Plan-Do-Study-Act cycles to contextually modify and adapt Robson classification into the existing workflow to improve the process of documentation and data collection for CS in the first 6 months (January 2019-June 2019) and then to use these data to develop strategies to reduce CS rate below 30% in the next 18 months.To evaluate the impact of developed strategies, the team plotted the data on Statistical Process Control (XmR) chart. The baseline mean CS rate was 32.6%. The team observed a shift in the CS rate data twice, between April 2020 and December 2020 and between August 2021 and February 2021 with the mean 27.8% and 28.9%, respectively. October 2021 onwards, the team also observed a sustained reduction in the CS rate in women undergoing CS who had one previous CS. The mean CS rate reduced from 94% to 86%.The reductions in the CS rate were not sustained and followed by an increase again. The project highlighted the complexity of the factors related to CS delivery and the multidimensional barriers of sustaining the reduction in the CS rate. This is a well-sustained ongoing QI intervention and the team is further working on identifying the underlying factors to improve the efficacy of the interventions to sustain the reduction in the CS rate.This hospital represents the general population of North India seeking care in public healthcare facilities. Therefore, despite being a single-centre study, the population served and interpretations drawn from this study are generalisable to other hospitals with similar settings.


Asunto(s)
Cesárea , Mejoramiento de la Calidad , Embarazo , Humanos , Femenino , Hospitales , India
4.
Vaccine X ; 14: 100298, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37113741

RESUMEN

Background and Objectives: Human papillomavirus (HPV) is implicated in the development of both anogenital and oropharyngeal cancers. Although HPV vaccination prevents the majority of anogenital and head and neck cancers (HNC), vaccination rates remain low, especially among males. Known barriers to vaccination are knowledge gaps and vaccine acceptability. The objective of this study is to explore parental knowledge, perceptions, and decision-making processes about HPV and HPV vaccination for both anogenital and HNC. Methods: This qualitative study recruited parents of children and adolescents aged 8-18 to participate in semi-structured telephone interviews. Data were analyzed using thematic analyses, informed by an inductive approach. Results: A total of 31 parents participated in the study. Six themes emerged: 1) knowledge about HPV vaccines, 2) perceptions and attitudes toward cancers, 3) role of child's sex in HPV vaccination, 4) decision-making processes around HPV vaccination, 5) communication with health care providers about HPV vaccines, and 6) influence of social networks. There were significant knowledge gaps about the vaccine's indications and effects, especially for males and HNC prevention. Parents had concerns related to risks of the HPV vaccine. They cited pediatricians as important sources of information about vaccination and critical to their decision-making. Conclusions: This study identified many parental knowledge gaps related to HPV vaccination, with information about males, HNC prevention, and risks particularly lacking. As parents identified pediatricians as the most important sources of information regarding HPV vaccination, this should empower pediatricians to educate families about this important preventive health measure, with a focus on addressing concerns about vaccine risks.

5.
Indian J Sex Transm Dis AIDS ; 39(1): 44-49, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30187026

RESUMEN

CONTEXT: Pruritic papular eruption (PPE) is a chronic eruption of papular and pruritic lesions of unknown etiology, symmetrically distributed over trunk and extremities. These are common cutaneous manifestations in HIV patients. It is an important cause of HIV-related morbidity. PPE can be the first marker of HIV. Their etiology, histopathological findings, and associated factors vary from region to region. There are no clear data available on the etiology, exact spectrum of the condition, histopathological findings, or treatment of PPE. AIMS: The study is aimed at documenting the etiology, CD4 count, and its histopathological correlation in HIV-infected patients. SETTINGS AND DESIGN: An observational study conducted in Government Medical College, Patiala. SUBJECTS AND METHODS: Two-year data regarding history, HIV status, cluster of differentiation 4 (CD4) cell count, and skin biopsy of clinically suspected PPE patients with known HIV status were analyzed. STATISTICAL ANALYSIS USED: All the results were then statistically analyzed. Categorical data were analyzed by Chi-square test, and one-way Spearman's rho test was used for multiple group comparison. RESULTS: Data of 50 eligible patients were analyzed. The majority of the patients were female (between 21 and 50 years of age). The most common histopathological patterns were of papular urticaria, scabies, and drug reaction, and the others less common PPE were polymorphic light eruption and eosinophilic folliculitis. Patients with papular urticaria (32%) had significantly lower mean CD4 counts (157 cells/mm3), while in scabies, the mean CD4 count (376 cells/mm3) was higher. CONCLUSIONS: We conclude that histopathology helps in specifying the pattern of PPE and its etiology. It can be a marker of advanced HIV infection. Thus, correlation between the histopathology, clinical diagnosis, and CD4 counts helps to know the disease process.

6.
Eur Arch Otorhinolaryngol ; 273(10): 3167-73, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26932756

RESUMEN

Video head impulse test (vHIT) aids to assess all three pairs of semi-circular canals (SCCs) separately and can be utilized to find out the exact site of lesion in any three SCCs by measuring vestibulo ocular reflex (VOR) gain. VOR gain value of vHIT has been used to diagnose different vestibular pathologies. Hence, it is important to establish the test-retest reliability of the VOR gain parameters before it could be administered to the patients. Therefore, the aim of the present study was to obtain VOR gain data, correlate all planes in both sides of head (right and left) and assess the test-retest reliability of VOR gain measure using vHIT in 25 normal young adult participants. Video head impulse test tests were carried out with prototype ICS impulse video goggles with a camera speed of 250 frames/s, recording motion of the right eye in all three planes (lateral, right anterior left posterior, left anterior right posterior) for all the participants. vHIT testing was repeated for all the participants after 15 days. Statistical analysis revealed that mean VOR gain for right horizontal canal was higher than the left horizontal canal; right anterior canal was higher than left anterior canal and left anterior was higher than right posterior canal. Horizontal canals have more gain compared to anterior and posterior canals. There was no significant difference between the VOR gain of session 1 and session 2 for each SCC.


Asunto(s)
Prueba de Impulso Cefálico , Audición/fisiología , Reflejo Vestibuloocular/fisiología , Adolescente , Adulto , Femenino , Humanos , Masculino , Valores de Referencia , Reproducibilidad de los Resultados , Canales Semicirculares/fisiología , Vestíbulo del Laberinto/fisiología , Adulto Joven
7.
J Acoust Soc Am ; 140(6): 4298, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-28039998

RESUMEN

The main aim of this study was to use spectral smearing to evaluate the efficacy of a spectral ripple test (SRt) using stationary sounds and a recent variant with gliding ripples called the spectro-temporal ripple test (STRt) in measuring reduced spectral resolution. In experiment 1 the highest detectable ripple density was measured using four amounts of spectral smearing (unsmeared, mild, moderate, and severe). The thresholds worsened with increasing smearing and were similar for the SRt and the STRt across the three conditions with smearing. For unsmeared stimuli, thresholds were significantly higher (better) for the STRt than for the SRt. An amplitude fluctuation at the outputs of simulated (gammatone) auditory filters centered above 6400 Hz was identified as providing a potential detection cue for the STRt stimuli. Experiment 2 used notched noise with energy below and above the passband of the SRt and STRt stimuli to reduce confounding cues in the STRt. Thresholds were almost identical for the STRt and SRt for both unsmeared and smeared stimuli, indicating that the confounding cue for the STRt was eliminated by the notched noise. Thresholds obtained with notched noise present could be predicted reasonably accurately using an excitation-pattern model.

8.
Antimicrob Agents Chemother ; 58(11): 6861-9, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25182647

RESUMEN

Resistance to the 2'-F-2'-C-methylguanosine monophosphate nucleotide hepatitis C virus (HCV) inhibitors PSI-352938 and PSI-353661 was associated with a combination of amino acid changes (changes of S to G at position 15 [S15G], C223H, and V321I) within the genotype 2a nonstructural protein 5B (NS5B), an RNA-dependent RNA polymerase. To understand the role of these residues in viral replication, we examined the effects of single and multiple point mutations on replication fitness and inhibition by a series of nucleotide analog inhibitors. An acidic residue at position 15 reduced replicon fitness, consistent with its proximity to the RNA template. A change of the residue at position 223 to an acidic or large residue reduced replicon fitness, consistent with its proposed proximity to the incoming nucleoside triphosphate (NTP). A change of the residue at position 321 to a charged residue was not tolerated, consistent with its position within a hydrophobic cavity. This triple resistance mutation was specific to both genotype 2a virus and 2'-F-2'-C-methylguanosine inhibitors. A crystal structure of the NS5B S15G/C223H/V321I mutant of the JFH-1 isolate exhibited rearrangement to a conformation potentially consistent with short primer-template RNA binding, which could suggest a mechanism of resistance accomplished through a change in the NS5B conformation, which was better tolerated by genotype 2a virus than by viruses of other genotypes.


Asunto(s)
Farmacorresistencia Viral/genética , Hepacivirus/genética , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/ultraestructura , Replicación Viral/genética , Antivirales/farmacología , Cristalografía por Rayos X , Óxidos P-Cíclicos/farmacología , Guanosina Monofosfato/análogos & derivados , Guanosina Monofosfato/farmacología , Hepacivirus/efectos de los fármacos , Hepacivirus/crecimiento & desarrollo , Humanos , Nucleósidos/farmacología , Estructura Terciaria de Proteína , ARN Viral/genética , Proteínas de Unión al ARN/genética
9.
J Med Chem ; 57(5): 2136-60, 2014 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-24476391

RESUMEN

HTS screening identified compound 2a (piperazinone derivative) as a low micromolar HCV genotype 1 (GT-1) inhibitor. Resistance mapping studies suggested that this piperazinone chemotype targets the HCV nonstructural protein NS4B. Extensive SAR studies were performed around 2a and the amide function and the C-3/C-6 cis stereochemistry of the piperazinone core were essential for HCV activity. A 10-fold increase in GT-1 potency was observed when the chiral phenylcyclopropyl amide side chain of 2a was replaced with p-fluorophenylisoxazole-carbonyl moiety (67). Replacing the C-6 nonpolar hydrophobic moiety of 67 with a phenyl moiety (95) did not diminish the GT-1 potency. A heterocyclic thiophene moiety (103) and an isoxazole moiety (108) were incorporated as isosteric replacements for the C-6 phenyl moiety (95), resulting in significant improvement in GT-1b and 1a potency. However, the piperazonone class of compounds lacks GT-2 activity and, consequently, were not pursued further into development.


Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Piperazinas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Descubrimiento de Drogas , Piperazinas/química , Relación Estructura-Actividad
10.
J Med Chem ; 57(5): 1826-35, 2014 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-24079820

RESUMEN

Conformationally restricted 2'-spironucleosides and their prodrugs were synthesized as potential anti-HCV agents. Although the replicon activity of the new agents containing pyrimidine bases was modest, the triphosphate of a 2'-oxetane cytidine analogue demonstrated potent intrinsic biochemical activity against the NS5B polymerase, with IC50 = 8.48 µM. Activity against NS5B bearing the S282T mutation was reduced. Phosphoramidate prodrugs of a 2'-oxetane 2-amino-6-O-methyl-purine nucleoside demonstrated potent anti-HCV activity in vitro, and the corresponding triphosphate retained similar potent activity against both wild-type and S282T HCV NS5B polymerase.


Asunto(s)
Antivirales/farmacología , Citidina/farmacología , Diseño de Fármacos , Hepacivirus/efectos de los fármacos , Antivirales/química , Línea Celular , Citidina/química , Citidina/genética , Éteres/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masa por Ionización de Electrospray
11.
Bioorg Med Chem Lett ; 22(18): 5924-9, 2012 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-22892115

RESUMEN

The 3',5'-cyclic phosphate prodrug 9-[ß-d-2'-deoxy-2'-α-fluoro-2'-ß-C-methylribofuranosyl]-2-amino-6-ethoxypurine, PSI-352938 1, has demonstrated promising anti-HCV efficacy in vitro and in human clinical trials. A structure-activity relationship study of the nucleoside 3',5'-cyclic phosphate series of ß-d-2'-deoxy-2'-α-fluoro-2'-ß-C-methylribofuranosyl nucleoside prodrugs was undertaken and the anti-HCV activity and in vitro safety profile were assessed. Cycloalkyl 3',5'-cyclic phosphate prodrugs were shown to be significantly more potent as inhibitors of HCV replication than branched and straight chain alkyl 3',5'-cyclic phosphate prodrugs. No cytotoxicity and mitochondrial toxicity for prodrugs 12, 13 and 19 were observed at concentrations up to 100 µm in vitro. Cycloalkyl esters of 3',5'-cyclic phosphate nucleotide prodrugs demonstrated the ability to produce high levels of active triphosphate in clone-A cells and primary human hepatocytes. Compounds 12, 13 and 19 also demonstrated the ability to effectively deliver in vivo high levels of active nucleoside phosphates to rat liver.


Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Nucleótidos Cíclicos/farmacología , Profármacos/farmacología , Animales , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Humanos , Hígado/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Nucleótidos Cíclicos/síntesis química , Nucleótidos Cíclicos/química , Profármacos/síntesis química , Profármacos/química , Ratas , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacos
12.
Antimicrob Agents Chemother ; 56(7): 3767-75, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22526308

RESUMEN

PSI-352938 is a novel cyclic phosphate prodrug of ß-D-2'-deoxy-2'-α-fluoro-2'-ß-C-methylguanosine-5'-monophosphate with potent anti-HCV activity. In order to inhibit the NS5B RNA-dependent RNA polymerase, PSI-352938 must be metabolized to the active triphosphate form, PSI-352666. During in vitro incubations with PSI-352938, significantly larger amounts of PSI-352666 were formed in primary hepatocytes than in clone A hepatitis C virus (HCV) replicon cells. Metabolism and biochemical assays were performed to define the molecular mechanism of PSI-352938 activation. The first step, removal of the isopropyl group on the 3',5'-cyclic phosphate moiety, was found to be cytochrome P450 (CYP) 3A4 dependent, with other CYP isoforms unable to catalyze the reaction. The second step, opening of the cyclic phosphate ring, was catalyzed by phosphodiesterases (PDEs) 2A1, 5A, 9A, and 11A4, all known to be expressed in the liver. The role of these enzymes in the activation of PSI-352938 was confirmed in primary human hepatocytes, where prodrug activation was reduced by inhibitors of CYP3A4 and PDEs. The third step, removal of the O(6)-ethyl group on the nucleobase, was shown to be catalyzed by adenosine deaminase-like protein 1. The resulting monophosphate was consecutively phosphorylated to the diphosphate and to the triphosphate PSI-352666 by guanylate kinase 1 and nucleoside diphosphate kinase, respectively. In addition, formation of nucleoside metabolites was observed in primary hepatocytes, and ecto-5'-nucleotidase was able to dephosphorylate the monophosphate metabolites. Since CYP3A4 is highly expressed in the liver, the CYP3A4-dependent metabolism of PSI-352938 makes it an effective liver-targeted prodrug, in part accounting for the potent antiviral activity observed clinically.


Asunto(s)
Antivirales/metabolismo , Óxidos P-Cíclicos/metabolismo , Hepacivirus/efectos de los fármacos , Nucleósidos/metabolismo , Células Cultivadas , Citocromo P-450 CYP3A/metabolismo , Guanilato-Quinasas/metabolismo , Hepatocitos/metabolismo , Humanos , Nucleósido-Difosfato Quinasa/metabolismo , Hidrolasas Diéster Fosfóricas/metabolismo
13.
Bioorg Med Chem Lett ; 22(8): 2938-42, 2012 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-22425564

RESUMEN

The HCV non-structural protein NS5A has been established as a viable target for the development of direct acting antiviral therapy. From computational modeling studies strong intra-molecular hydrogen bonds were found to be a common structural moiety within known NS5A inhibitors that have low pico-molar replicon potency. Efforts to reproduce these γ-turn-like substructures provided a novel NS5A inhibitor based on a fluoro-olefin isostere. This fluoro-olefin containing inhibitor exhibited picomolar activity (EC(50)=79 pM) against HCV genotype 1b replicon without measurable cytotoxicity. This level of activity is comparable to the natural peptide-based inhibitors currently under clinic evaluation, and demonstrates that a peptidomimetic approach can serve as a useful strategy to produce potent and structurally unique inhibitors of HCV NS5A.


Asunto(s)
Alquenos/química , Flúor/química , Hepacivirus/efectos de los fármacos , Peptidomiméticos/química , Peptidomiméticos/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Alquenos/farmacología , Flúor/farmacología , Humanos , Enlace de Hidrógeno , Modelos Moleculares
14.
Antimicrob Agents Chemother ; 56(6): 3359-68, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22430955

RESUMEN

PSI-7977, a prodrug of 2'-F-2'-C-methyluridine monophosphate, is the purified diastereoisomer of PSI-7851 and is currently being investigated in phase 3 clinical trials for the treatment of hepatitis C. In this study, we profiled the activity of PSI-7977 and its ability to select for resistance using a number of different replicon cells. Results showed that PSI-7977 was active against genotype (GT) 1a, 1b, and 2a (strain JFH-1) replicons and chimeric replicons containing GT 2a (strain J6), 2b, and 3a NS5B polymerase. Cross-resistance studies using GT 1b replicons confirmed that the S282T change conferred resistance to PSI-7977. Subsequently, we evaluated the ability of PSI-7977 to select for resistance using GT 1a, 1b, and 2a (JFH-1) replicon cells. S282T was the common mutation selected among all three genotypes, but while it conferred resistance to PSI-7977 in GT 1a and 1b, JFH-1 GT 2a S282T showed only a very modest shift in 50% effective concentration (EC(50)) for PSI-7977. Sequence analysis of the JFH-1 NS5B region indicated that additional amino acid changes were selected both prior to and after the emergence of S282T. These include T179A, M289L, I293L, M434T, and H479P. Residues 179, 289, and 293 are located within the finger and palm domains, while 434 and 479 are located on the surface of the thumb domain. Data from the JFH-1 replicon variants showed that amino acid changes within the finger and palm domains together with S282T were required to confer resistance to PSI-7977, while the mutations on the thumb domain serve to enhance the replication capacity of the S282T replicons.


Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Uridina Monofosfato/análogos & derivados , Línea Celular , Genotipo , Humanos , Replicón/efectos de los fármacos , Replicón/genética , Sofosbuvir , Uridina Monofosfato/farmacología , Replicación Viral/efectos de los fármacos
15.
J Virol ; 85(23): 12334-42, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21957306

RESUMEN

PSI-352938, a cyclic phosphate nucleotide, and PSI-353661, a phosphoramidate nucleotide, are prodrugs of ß-D-2'-deoxy-2'-α-fluoro-2'-ß-C-methylguanosine-5'-monophosphate. Both compounds are metabolized to the same active 5'-triphosphate, PSI-352666, which serves as an alternative substrate inhibitor of the NS5B RNA-dependent RNA polymerase during HCV replication. PSI-352938 and PSI-353661 retained full activity against replicons containing the S282T substitution, which confers resistance to certain 2'-substituted nucleoside/nucleotide analogs. PSI-352666 was also similarly active against both wild-type and S282T NS5B polymerases. In order to identify mutations that confer resistance to these compounds, in vitro selection studies were performed using HCV replicon cells. While no resistant genotype 1a or 1b replicons could be selected, cells containing genotype 2a JFH-1 replicons cultured in the presence of PSI-352938 or PSI-353661 developed resistance to both compounds. Sequencing of the NS5B region identified a number of amino acid changes, including S15G, R222Q, C223Y/H, L320I, and V321I. Phenotypic evaluation of these mutations indicated that single amino acid changes were not sufficient to significantly reduce the activity of PSI-352938 and PSI-353661. Instead, a combination of three amino acid changes, S15G/C223H/V321I, was required to confer a high level of resistance. No cross-resistance exists between the 2'-F-2'-C-methylguanosine prodrugs and other classes of HCV inhibitors, including 2'-modified nucleoside/-tide analogs such as PSI-6130, PSI-7977, INX-08189, and IDX-184. Finally, we determined that in genotype 1b replicons, the C223Y/H mutation failed to support replication, and although the A15G/C223H/V321I triple mutation did confer resistance to PSI-352938 and PSI-353661, this mutant replicated at only about 10% efficiency compared to the wild type.


Asunto(s)
Óxidos P-Cíclicos/farmacología , Farmacorresistencia Viral , Guanosina Monofosfato/análogos & derivados , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Mutación/genética , Nucleósidos/farmacología , ARN Viral/genética , Replicón/efectos de los fármacos , Antivirales/farmacología , Guanosina Monofosfato/farmacología , Hepatitis C/tratamiento farmacológico , Hepatitis C/genética , Hepatitis C/virología , Humanos , Fenotipo , Profármacos/farmacología , Conformación Proteica , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/metabolismo , Replicón/genética , Replicación Viral/efectos de los fármacos , Replicación Viral/genética
16.
Antiviral Res ; 91(2): 120-32, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21600932

RESUMEN

PSI-353661, a phosphoramidate prodrug of 2'-deoxy-2'-fluoro-2'-C-methylguanosine-5'-monophosphate, is a highly active inhibitor of genotype 1a, 1b, and 2a HCV RNA replication in the replicon assay and of genotype 1a and 2a infectious virus replication. PSI-353661 is active against replicons harboring the NS5B S282T or S96T/N142T amino acid alterations that confer decreased susceptibility to nucleoside/tide analogs as well as mutations that confer resistance to non-nucleoside inhibitors of NS5B. Replicon clearance studies show that PSI-353661 was able to clear cells of HCV replicon RNA and prevent a rebound in replicon RNA. PSI-353661 showed no toxicity toward bone marrow stem cells or mitochondrial toxicity. The metabolism to the active 5'-triphosphate involves hydrolysis of the carboxyl ester by cathepsin A (Cat A) and carboxylesterase 1 (CES1) followed by a putative nucleophilic attack on the phosphorus by the carboxyl group resulting in the elimination of phenol and the alaninyl phosphate metabolite, PSI-353131. Histidine triad nucleotide-binding protein 1 (Hint 1) then removes the amino acid moiety, which is followed by hydrolysis of the methoxyl group at the O(6)-position of the guanine base by adenosine deaminase-like protein 1 (ADAL1) to give 2'-deoxy-2'-fluoro-2'-C-methylguanosine-5'-monophosphate. The monophosphate is phosphorylated to the diphosphate by guanylate kinase. Nucleoside diphosphate kinase is the primary enzyme involved in phosphorylation of the diphosphate to the active triphosphate, PSI-352666. PSI-352666 is equally active against wild-type NS5B and NS5B containing the S282T amino acid alteration.


Asunto(s)
Antivirales/farmacología , Guanosina Monofosfato/análogos & derivados , Hepacivirus/efectos de los fármacos , Profármacos/farmacología , Replicación Viral/efectos de los fármacos , Biotransformación , Catepsina A/metabolismo , Cromatografía Líquida de Alta Presión , Clonación Molecular , Evaluación Preclínica de Medicamentos , Guanosina Monofosfato/antagonistas & inhibidores , Guanosina Monofosfato/farmacología , Guanilato-Quinasas/metabolismo , Células Hep G2 , Hepacivirus/genética , Hepacivirus/fisiología , Hepatocitos/efectos de los fármacos , Humanos , Ácido Láctico/metabolismo , Luciferasas/metabolismo , Pruebas de Sensibilidad Microbiana , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mutación , Proteínas del Tejido Nervioso/metabolismo , Fenol/metabolismo , Fosforilación , Profármacos/química , Replicón , Proteínas no Estructurales Virales/antagonistas & inhibidores
17.
Antimicrob Agents Chemother ; 55(6): 2566-75, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21444700

RESUMEN

PSI-352938 is a novel cyclic phosphate prodrug of ß-D-2'-deoxy-2'-α-fluoro-2'-ß-C-methylguanosine 5'-monophosphate that has potent activity against hepatitis C virus (HCV) in vitro. The studies described here characterize the in vitro anti-HCV activity of PSI-352938, alone and in combination with other inhibitors of HCV, and the cross-resistance profile of PSI-352938. The effective concentration required to achieve 50% inhibition for PSI-352938, determined using genotype 1a-, 1b-, and 2a-derived replicons stably expressed in the Lunet cell line, were 0.20, 0.13, and 0.14 µM, respectively. The active 5'-triphosphate metabolite, PSI-352666, inhibited recombinant NS5B polymerase from genotypes 1 to 4 with comparable 50% inhibitory concentrations. In contrast, PSI-352938 did not inhibit the replication of hepatitis B virus or human immunodeficiency virus in vitro. PSI-352666 did not significantly affect the activity of human DNA and RNA polymerases. PSI-352938 and its cyclic phosphate metabolites did not affect the cyclic GMP-mediated activation of protein kinase G. Clearance studies using replicon cells demonstrated that PSI-352938 cleared cells of HCV replicon RNA and prevented replicon rebound. An additive to synergistic effect was observed when PSI-352938 was combined with other classes of HCV inhibitors, including alpha interferon, ribavirin, NS3/4A inhibitors, an NS5A inhibitor, and nucleoside/nucleotide and nonnucleoside inhibitors. Cross-resistance studies showed that PSI-352938 remained fully active against replicons containing the S282T or the S96T/N142T amino acid alteration. Replicons that contain mutations conferring resistance to various classes of nonnucleoside inhibitors also remained sensitive to inhibition by PSI-352938. PSI-352938 is currently being evaluated in a phase I clinical study in genotype 1-infected individuals.


Asunto(s)
Antivirales/farmacología , Óxidos P-Cíclicos/farmacología , Desoxiguanosina/análogos & derivados , Hepacivirus/efectos de los fármacos , Nucleósidos/farmacología , Profármacos/farmacología , ARN Viral/biosíntesis , Replicón/efectos de los fármacos , Desoxiguanosina/farmacología , Farmacorresistencia Viral , Humanos
18.
ACS Med Chem Lett ; 2(2): 130-5, 2011 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-24900291

RESUMEN

Hepatitis C virus afflicts approximately 180 million people worldwide, and the development of direct acting antivirals may offer substantial benefit compared to the current standard of care. Accordingly, prodrugs of 2'-deoxy-2'-fluoro-2'-C-methylguanosine monophosphate analogues were prepared and evaluated for their anti-HCV efficacy and tolerability. These prodrugs demonstrated >1000 fold greater potency than the parent nucleoside in a cell-based replicon assay as a result of higher intracellular triphosphate levels. Further optimization led to the discovery of the clinical candidate PSI-353661, which has demonstrated strong in vitro inhibition against HCV without cytotoxicity and equipotent activity against both the wild type and the known S282T nucleoside/tide resistant replicon. PSI-353661 is currently in preclinical development for the treatment of HCV.

19.
Bioorg Med Chem Lett ; 20(24): 7376-80, 2010 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-21050754

RESUMEN

A series of novel 2'-deoxy-2'-α-fluoro-2'-ß-C-methyl 3',5'-cyclic phosphate nucleotide prodrug analogs were synthesized and evaluated for their in vitro anti-HCV activity and safety. These prodrugs demonstrated a 10-100-fold greater potency than the parent nucleoside in a cell-based replicon assay due to higher cellular triphosphate levels. Our structure-activity relationship (SAR) studies provided compounds that gave high levels of active triphosphate in rat liver when administered orally to rats. These studies ultimately led to the selection of the clinical development candidate 24a (PSI-352938).


Asunto(s)
Antivirales/química , Óxidos P-Cíclicos/química , Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Nucleósidos/química , Nucleótidos Cíclicos/química , Profármacos/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Antivirales/farmacocinética , Antivirales/toxicidad , Línea Celular Tumoral , Cristalografía por Rayos X , Óxidos P-Cíclicos/farmacocinética , Óxidos P-Cíclicos/toxicidad , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/toxicidad , Humanos , Conformación Molecular , Nucleósidos/farmacocinética , Nucleósidos/toxicidad , Nucleótidos Cíclicos/síntesis química , Nucleótidos Cíclicos/toxicidad , Profármacos/farmacocinética , Profármacos/farmacología , Ratas , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismo
20.
J Med Chem ; 53(19): 7202-18, 2010 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-20845908

RESUMEN

Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. ß-d-2'-Deoxy-2'-α-fluoro-2'-ß-C-methyl nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5'-phosphate derivative of the ß-d-2'-deoxy-2'-α-fluoro-2'-ß-C-methyluridine nucleoside were prepared and showed significant potency in the HCV subgenomic replicon assay (<1 µM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixture 14 was crystallized, and an X-ray structure was determined establishing the phosphoramidate stereochemistry as Sp, thus correlating for the first time the stereochemistry of a phosphoramidate prodrug with biological activity. 51 (PSI-7977) was selected as a clinical development candidate.


Asunto(s)
Antivirales/síntesis química , Hepacivirus/efectos de los fármacos , Profármacos/síntesis química , Uridina Monofosfato/análogos & derivados , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Línea Celular , Cristalografía por Rayos X , Perros , Farmacorresistencia Viral , Ésteres , Hepacivirus/genética , Hepatocitos/metabolismo , Humanos , Técnicas In Vitro , Hígado/metabolismo , Macaca fascicularis , Mutación , Profármacos/farmacocinética , Profármacos/farmacología , Ratas , Replicón , Sofosbuvir , Estereoisomerismo , Relación Estructura-Actividad , Uridina Monofosfato/síntesis química , Uridina Monofosfato/farmacocinética , Uridina Monofosfato/farmacología , Proteínas no Estructurales Virales/genética
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