Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 18 de 18
Filtrar
1.
Nature ; 615(7953): 678-686, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36922586

RESUMEN

Dengue is a major health threat and the number of symptomatic infections caused by the four dengue serotypes is estimated to be 96 million1 with annually around 10,000 deaths2. However, no antiviral drugs are available for the treatment or prophylaxis of dengue. We recently described the interaction between non-structural proteins NS3 and NS4B as a promising target for the development of pan-serotype dengue virus (DENV) inhibitors3. Here we present JNJ-1802-a highly potent DENV inhibitor that blocks the NS3-NS4B interaction within the viral replication complex. JNJ-1802 exerts picomolar to low nanomolar in vitro antiviral activity, a high barrier to resistance and potent in vivo efficacy in mice against infection with any of the four DENV serotypes. Finally, we demonstrate that the small-molecule inhibitor JNJ-1802 is highly effective against viral infection with DENV-1 or DENV-2 in non-human primates. JNJ-1802 has successfully completed a phase I first-in-human clinical study in healthy volunteers and was found to be safe and well tolerated4. These findings support the further clinical development of JNJ-1802, a first-in-class antiviral agent against dengue, which is now progressing in clinical studies for the prevention and treatment of dengue.


Asunto(s)
Antivirales , Virus del Dengue , Dengue , Primates , Proteínas no Estructurales Virales , Animales , Humanos , Ratones , Antivirales/efectos adversos , Antivirales/farmacología , Antivirales/uso terapéutico , Ensayos Clínicos Fase I como Asunto , Dengue/tratamiento farmacológico , Dengue/prevención & control , Dengue/virología , Virus del Dengue/clasificación , Virus del Dengue/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Farmacorresistencia Viral , Técnicas In Vitro , Terapia Molecular Dirigida , Primates/virología , Unión Proteica/efectos de los fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismo , Replicación Viral
2.
Nature ; 598(7881): 504-509, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34616043

RESUMEN

Dengue virus causes approximately 96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue1,2. There are no antiviral agents available to prevent or treat dengue. Here, we describe a highly potent dengue virus inhibitor (JNJ-A07) that exerts nanomolar to picomolar activity against a panel of 21 clinical isolates that represent the natural genetic diversity of known genotypes and serotypes. The molecule has a high barrier to resistance and prevents the formation of the viral replication complex by blocking the interaction between two viral proteins (NS3 and NS4B), thus revealing a previously undescribed mechanism of antiviral action. JNJ-A07 has a favourable pharmacokinetic profile that results in outstanding efficacy against dengue virus infection in mouse infection models. Delaying start of treatment until peak viraemia results in a rapid and significant reduction in viral load. An analogue is currently in further development.


Asunto(s)
Antivirales/farmacología , Virus del Dengue/clasificación , Virus del Dengue/efectos de los fármacos , Dengue/virología , Proteínas de la Membrana/metabolismo , Proteínas no Estructurales Virales/metabolismo , Animales , Antivirales/farmacocinética , Antivirales/uso terapéutico , Dengue/tratamiento farmacológico , Virus del Dengue/genética , Virus del Dengue/metabolismo , Modelos Animales de Enfermedad , Femenino , Masculino , Proteínas de la Membrana/antagonistas & inhibidores , Ratones , ARN Helicasas/antagonistas & inhibidores , ARN Helicasas/metabolismo , Serina Endopeptidasas/metabolismo , Carga Viral/efectos de los fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Viremia/tratamiento farmacológico , Viremia/virología , Replicación Viral/efectos de los fármacos
4.
Nat Commun ; 15(1): 6080, 2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-39030239

RESUMEN

Dengue fever represents a significant medical and socio-economic burden in (sub)tropical regions, yet antivirals for treatment or prophylaxis are lacking. JNJ-A07 was described as highly active against the different genotypes within each serotype of the disease-causing dengue virus (DENV). Based on clustering of resistance mutations it has been assumed to target DENV non-structural protein 4B (NS4B). Using a photoaffinity labeling compound with high structural similarity to JNJ-A07, here we demonstrate binding to NS4B and its precursor NS4A-2K-NS4B. Consistently, we report recruitment of the compound to intracellular sites enriched for these proteins. We further specify the mechanism-of-action of JNJ-A07, which has virtually no effect on viral polyprotein cleavage, but targets the interaction between the NS2B/NS3 protease/helicase complex and the NS4A-2K-NS4B cleavage intermediate. This interaction is functionally linked to de novo formation of vesicle packets (VPs), the sites of DENV RNA replication. JNJ-A07 blocks VPs biogenesis with little effect on established ones. A similar mechanism-of-action was found for another NS4B inhibitor, NITD-688. In summary, we unravel the antiviral mechanism of these NS4B-targeting molecules and show how DENV employs a short-lived cleavage intermediate to carry out an early step of the viral life cycle.


Asunto(s)
Antivirales , Virus del Dengue , Dengue , Proteínas no Estructurales Virales , Replicación Viral , Virus del Dengue/efectos de los fármacos , Virus del Dengue/genética , Virus del Dengue/fisiología , Proteínas no Estructurales Virales/metabolismo , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/antagonistas & inhibidores , Replicación Viral/efectos de los fármacos , Antivirales/farmacología , Humanos , Dengue/virología , Dengue/tratamiento farmacológico , Serogrupo , ARN Helicasas/metabolismo , ARN Helicasas/antagonistas & inhibidores , ARN Helicasas/genética , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/genética , Unión Proteica , Animales , Orgánulos/metabolismo , Orgánulos/efectos de los fármacos , Proteasas Virales , Aminofenoles , Proteínas de la Membrana , Indoles , ARN Helicasas DEAD-box , Nucleósido-Trifosfatasa , Butiratos
5.
J Med Chem ; 67(5): 4063-4082, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38482827

RESUMEN

Dengue is a global public health threat, with about half of the world's population at risk of contracting this mosquito-borne viral disease. Climate change, urbanization, and global travel accelerate the spread of dengue virus (DENV) to new areas, including southern parts of Europe and the US. Currently, no dengue-specific small-molecule antiviral for prophylaxis or treatment is available. Here, we report the discovery of JNJ-1802 as a potent, pan-serotype DENV inhibitor (EC50's ranging from 0.057 to 11 nM against the four DENV serotypes). The observed oral bioavailability of JNJ-1802 across preclinical species, its low clearance in human hepatocytes, the absence of major in vitro pharmacology safety alerts, and a dose-proportional increase in efficacy against DENV-2 infection in mice were all supportive of its selection as a development candidate against dengue. JNJ-1802 is being progressed in clinical studies for the prevention or treatment of dengue.


Asunto(s)
Virus del Dengue , Dengue , Hidrocarburos Halogenados , Indoles , Ratones , Humanos , Animales , Serogrupo , Dengue/tratamiento farmacológico
6.
J Org Chem ; 78(2): 212-23, 2013 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-23227990

RESUMEN

A straightforward, easy, and practical access to various amino acid analogues (methionine, leucine, lysine, and arginine) from a unique fluorinated cyclopropane scaffold is described. Moreover, the synthesis, for the first time, of one tripeptide incorporating a fluorinated cyclopropane amino acid (FCAA) analogue is reported.


Asunto(s)
Aminoácidos/química , Aminoácidos/síntesis química , Arginina/química , Ciclopropanos/química , Hidrocarburos Fluorados/química , Leucina/química , Metionina/química , Oligopéptidos/química , Oligopéptidos/síntesis química , Peptidomiméticos/química , Peptidomiméticos/síntesis química , Halogenación , Estructura Molecular
7.
Proc Natl Acad Sci U S A ; 107(1): 308-13, 2010 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-19966279

RESUMEN

Six-helix bundle (6HB) formation is an essential step for many viruses that rely on a class I fusion protein to enter a target cell and initiate replication. Because the binding modes of small molecule inhibitors of 6HB formation are largely unknown, precisely how they disrupt 6HB formation remains unclear, and structure-based design of improved inhibitors is thus seriously hampered. Here we present the high resolution crystal structure of TMC353121, a potent inhibitor of respiratory syncytial virus (RSV), bound at a hydrophobic pocket of the 6HB formed by amino acid residues from both HR1 and HR2 heptad-repeats. Binding of TMC353121 stabilizes the interaction of HR1 and HR2 in an alternate conformation of the 6HB, in which direct binding interactions are formed between TMC353121 and both HR1 and HR2. Rather than completely preventing 6HB formation, our data indicate that TMC353121 inhibits fusion by causing a local disturbance of the natural 6HB conformation.


Asunto(s)
Antivirales/metabolismo , Bencimidazoles/metabolismo , Piridinas/metabolismo , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Virus Sincitial Respiratorio Humano/metabolismo , Proteínas Virales de Fusión/química , Proteínas Virales de Fusión/metabolismo , Secuencia de Aminoácidos , Antivirales/química , Antivirales/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Fusión Celular , Cristalografía por Rayos X , Células HeLa , Humanos , Fusión de Membrana/fisiología , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Estructura Secundaria de Proteína , Piridinas/química , Piridinas/farmacología , Secuencias Repetitivas de Aminoácido , Virus Sincitial Respiratorio Humano/química , Alineación de Secuencia , Relación Estructura-Actividad , Proteínas Virales de Fusión/antagonistas & inhibidores , Proteínas Virales de Fusión/genética
8.
J Med Chem ; 66(13): 8808-8821, 2023 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-37389813

RESUMEN

In the absence of any approved dengue-specific treatment, the discovery and development of a novel small-molecule antiviral for the prevention or treatment of dengue are critical. We previously reported the identification of a novel series of 3-acyl-indole derivatives as potent and pan-serotype dengue virus inhibitors. We herein describe our optimization efforts toward preclinical candidates 24a and 28a with improved pan-serotype coverage (EC50's against the four DENV serotypes ranging from 0.0011 to 0.24 µM for 24a and from 0.00060 to 0.084 µM for 28a), chiral stability, and oral bioavailability in preclinical species, as well as showing a dose-proportional increase in efficacy against DENV-2 infection in vivo in mice.


Asunto(s)
Virus del Dengue , Dengue , Ratones , Animales , Serogrupo , Antivirales/farmacología , Antivirales/uso terapéutico , Dengue/tratamiento farmacológico , Indoles/farmacología , Indoles/uso terapéutico
9.
ACS Med Chem Lett ; 13(12): 1879-1884, 2022 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-36518706

RESUMEN

In continuation of our efforts of finding novel nucleoside inhibitors for the treatment of viral diseases, we initiated a discovery research program aimed at identifying novel nucleos(t)ide inhibitors for emerging diseases like Dengue and Chikungunya. Based on the previously reported 2'-spiro-oxetane uridine derivatives active against Hepatitis C Virus (HCV), we envisaged its sulfur analogue as an interesting congener both from a synthetic as well as biological point of view. Surprisingly, we found the 2'-spirothietane uridine derivatives not only to be active against HCV and Dengue virus (DENV), viruses belonging to the flavivirus family, but also to demonstrate activity against alphaviruses like Chikungunya virus (CHIKV) and Sindbis virus (SINV).

10.
Bioorg Med Chem Lett ; 19(9): 2492-6, 2009 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-19342234

RESUMEN

Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent (replicon EC(50)=400nM and 270nM, respectively) and selective (CC(50)>20muM) inhibitors of HCV replication. These data warrant further lead-optimization efforts.


Asunto(s)
Antivirales/síntesis química , Benzodiazepinas/química , Química Farmacéutica/métodos , Hepacivirus/metabolismo , Proteínas no Estructurales Virales/antagonistas & inhibidores , Acrilatos/química , Antivirales/farmacología , Cristalografía por Rayos X , Diseño de Fármacos , Hepacivirus/enzimología , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Estructura Molecular , Relación Estructura-Actividad
11.
Antimicrob Agents Chemother ; 52(12): 4420-31, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18852280

RESUMEN

The exogenous control of hepatitis C virus (HCV) replication can be mediated through the inhibition of the RNA-dependent RNA polymerase (RdRp) activity of NS5B. Small-molecule inhibitors of NS5B include nucleoside and nonnucleoside analogs. Here, we report the discovery of a novel class of HCV polymerase nonnucleoside inhibitors, 1,5-benzodiazepines (1,5-BZDs), identified by high-throughput screening of a library of small molecules. A fluorescence-quenching assay and X-ray crystallography revealed that 1,5-BZD 4a bound stereospecifically to NS5B next to the catalytic site. When introduced into replicons, mutations known to confer resistance against chemotypes that bind at this site were detrimental to inhibition by 1,5-BZD 7a. Using a panel of enzyme isolates that covered genotypes 1 to 6, we showed that compound 4a inhibited genotype 1 only. In mechanistic studies, 4a was found to inhibit the RdRp activity of NS5B noncompetitively with GTP and to inhibit the formation of the first phosphodiester bond during the polymerization cycle. The specificity for the HCV target was evaluated by profiling the 1,5-BZDs against other viral and human polymerases, as well as BZD receptors.


Asunto(s)
Benzodiazepinas/farmacología , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/metabolismo , Antivirales/farmacología , Benzodiazepinas/química , Benzodiazepinas/metabolismo , Sitios de Unión , Línea Celular Tumoral , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Genotipo , Hepacivirus/enzimología , Hepacivirus/genética , Hepacivirus/fisiología , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , ARN Polimerasa Dependiente del ARN/química , ARN Polimerasa Dependiente del ARN/genética , ARN Polimerasa Dependiente del ARN/metabolismo , Relación Estructura-Actividad , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacos
12.
J Med Chem ; 51(4): 875-96, 2008 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-18254606

RESUMEN

A preceding paper (Bonfanti et al. J. Med Chem. 2007, 50, 4572-4584) reported the optimization of the pharmacokinetic profile of substituted benzimidazoles by reducing their tissue retention. However, the modifications that were necessary to achieve this goal also led to a significant drop in anti-RSV activity. This paper describes a molecular modeling study followed by a lead optimization program that led to the recovery of the initial potent antiviral activity and the selection of TMC353121 as a clinical candidate.


Asunto(s)
Antivirales/síntesis química , Bencimidazoles/síntesis química , Morfolinas/síntesis química , Piridinas/síntesis química , Virus Sincitiales Respiratorios/efectos de los fármacos , Proteínas Virales de Fusión/genética , Internalización del Virus/efectos de los fármacos , Animales , Antivirales/química , Antivirales/farmacología , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Sitios de Unión , Farmacorresistencia Viral , Masculino , Modelos Moleculares , Morfolinas/farmacocinética , Morfolinas/farmacología , Mutación , Unión Proteica , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Virus Sincitiales Respiratorios/fisiología , Sigmodontinae , Relación Estructura-Actividad
13.
J Med Chem ; 50(19): 4572-84, 2007 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-17722899

RESUMEN

We previously reported the discovery of substituted benzimidazole fusion inhibitors with nanomolar activity against respiratory syncytial virus (Andries, K.; et al. Antiviral Res. 2003, 60, 209-219). A lead compound of the series was selected for preclinical evaluation. This drug candidate, JNJ-2408068 (formerly R170591, 1), showed long tissue retention times in several species (rat, dog, and monkey), creating cause for concern. We herein describe the optimization program to develop compounds with improved properties in terms of tissue retention. We have identified the aminoethyl-piperidine moiety as being responsible for the long tissue retention time of 1. We have investigated the replacement or the modification of this group, and we suggest that the pKa of this part of the molecules influences both the antiviral activity and the pharmacokinetic profile. We were able to identify new respiratory syncytial virus inhibitors with shorter half-lives in lung tissue.


Asunto(s)
Antivirales/síntesis química , Bencimidazoles/síntesis química , Piperidinas/síntesis química , Piridinas/síntesis química , Virus Sincitiales Respiratorios/efectos de los fármacos , Proteínas Virales de Fusión/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Células HeLa , Humanos , Riñón/metabolismo , Hígado/metabolismo , Pulmón/metabolismo , Masculino , Piperidinas/farmacocinética , Piperidinas/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Distribución Tisular
14.
Org Lett ; 17(12): 2968-71, 2015 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-26053226
15.
PLoS One ; 10(5): e0126959, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26010881

RESUMEN

BACKGROUND: The study assessed the antiviral activity of TMC353121, a respiratory syncytial virus (RSV) fusion inhibitor, in a preclinical non-human primate challenge model with a viral shedding pattern similar to that seen in humans, following continuous infusion (CI). METHODS: African green monkeys were administered TMC353121 through CI, in 2 studies. Study 1 evaluated the prophylactic and therapeutic efficacy of TMC353121 at a target plasma level of 50 ng/mL (n=15; Group 1: prophylactic arm [Px50], 0.033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 24 hours pre-infection to 10 days; Group 2: therapeutic arm [Tx50], 0.033 mg/mL TMC353121 from 24 hours postinfection to 8 days; Group 3: control [Vh1] vehicle, 24 hours post-infection to 8 days). Study 2 evaluated the prophylactic efficacy of TMC353121 at target plasma levels of 5 and 500 ng/mL (n=12; Group 1: prophylactic 5 arm [Px5], 0.0033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 72 hours pre-infection to 14 days; Group 2: prophylactic 500 arm [Px500], 0.33 mg/mL TMC353121; Group 3: control [Vh2] vehicle, 14 days). Bronchoalveolar lavage fluid and plasma were collected every 2 days from day 1 postinfection for pharmacokinetics and safety analysis. FINDINGS: TMC353121 showed a dose-dependent antiviral activity, varying from 1 log10 reduction of peak viral load to complete inhibition of the RSV replication. Complete inhibition of RSV shedding was observed for a relatively low plasma exposure (0.39 µg/mL) and was associated with a dose-dependent reduction in INFγ, IL6 and MIP1α. TMC353121 administered as CI for 16 days was generally well-tolerated. CONCLUSION: TMC353121 exerted dose-dependent antiviral effect ranging from full inhibition to absence of antiviral activity, in a preclinical model highly permissive for RSV replication. No new safety findings emerged from the study.


Asunto(s)
Antivirales/farmacología , Bencimidazoles/farmacología , Piridinas/farmacología , Virus Sincitiales Respiratorios/fisiología , Internalización del Virus/efectos de los fármacos , Animales , Antivirales/farmacocinética , Área Bajo la Curva , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Líquido del Lavado Bronquioalveolar/virología , Chlorocebus aethiops , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Pulmón/efectos de los fármacos , Pulmón/patología , Piridinas/administración & dosificación , Piridinas/farmacocinética , Virus Sincitiales Respiratorios/efectos de los fármacos , Factores de Tiempo , Esparcimiento de Virus/efectos de los fármacos
16.
Methods Mol Biol ; 1030: 429-38, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23821286

RESUMEN

Chikungunya virus (CHIKV) is a mosquito-borne Alphavirus that has already infected millions of people in recent large-scale epidemics in Africa, the islands of the Indian Ocean, South and Southeast Asia, and northern Italy. The infection is still ongoing in many countries, such as India. Although the fatal rate is approximately 0.1% in the La Réunion outbreak, it causes painful arthritis-like symptoms that can last for months or even years. Currently, neither vaccine nor approved antiviral therapy exists to protect humans from chikungunya infection. Therefore, there is an urgent unmet medical need for the development of antiviral drugs for pre-exposure prophylaxis and/or treatment of chikungunya infections. In this chapter, we describe a fully validated ATP/luminescence assay that is effective for high-throughput screening of CHIKV inhibitors. Protocols for growing CHIKV stocks and generating drug-resistant viral variants for modes of action studies of compounds are also described.


Asunto(s)
Antivirales/farmacología , Virus Chikungunya/efectos de los fármacos , Virus Chikungunya/genética , Farmacorresistencia Viral/genética , Ensayos Analíticos de Alto Rendimiento , Pruebas de Sensibilidad Microbiana/métodos , Mutación , Animales , Técnicas de Cultivo de Célula , Chlorocebus aethiops , Células Hep G2 , Humanos , Células Vero
17.
Org Lett ; 14(23): 6012-5, 2012 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-23151283

RESUMEN

An efficient "one-pot" selective functionalization at C3/C6 of imidazo[1,2-a]pyrazines has been developed via a palladium-catalyzed sequential Suzuki-Miyaura cross-coupling/direct C-H arylation, vinylation, and benzylation. The procedure remains effective in the presence of a methyl thioether group at C8, which may in turn be successfully engaged in a cross-coupling method to afford 3,6,8-trisubstituted imidazo[1,2-a]pyrazines. This work paves the way for the design of biologically relevant compounds in an imidazo[1,2-a]pyrazine series.


Asunto(s)
Imidazoles/química , Paladio/química , Pirazinas/química , Catálisis , Imidazoles/síntesis química , Estructura Molecular , Pirazinas/síntesis química
18.
Curr Opin Drug Discov Devel ; 12(4): 479-87, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19562644

RESUMEN

Human respiratory syncytial virus (hRSV) is a significant cause of respiratory illness in at-risk pediatric patients, immunocompromised adults and the elderly. No vaccine is currently available for the virus and treatment options are limited to the prophylactic treatment of at-risk infants with the mAb palivizumab (Synagis) and to therapeutic intervention with the nucleoside analog ribavirin (Rebetol). The clinical use of these agents is limited and a need exists for more effective treatment for the at-risk population. The merging of viral and cellular membranes is a crucial event in the hRSV life cycle that enables the virus to enter a host cell. The multistep fusion process is facilitated by the substantial refolding of a trimeric class I fusion protein (F protein), which is the main target of fusion inhibitors. Several small-molecule fusion inhibitors have been discovered, of which some have progressed significantly in the drug development process. BTA-9881 (Biota Holdings Ltd/MedImmune) and TMC-353121 (Johnson & Johnson) are the most advanced of this drug class. In addition, progress has been made in the development of next-generation antibodies such as motavizumab (Numax; MedImmune). This review will discuss the status and latest developments of compounds and antibodies that inhibit hRSV fusion.


Asunto(s)
Antivirales/farmacología , Diseño de Fármacos , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Proteínas Virales de Fusión/antagonistas & inhibidores , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antivirales/química , Antivirales/uso terapéutico , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Estructura Molecular , Pliegue de Proteína , Piridinas/química , Piridinas/farmacología , Piridinas/uso terapéutico , Virus Sincitial Respiratorio Humano/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/uso terapéutico
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA