RESUMEN
We recently developed compound FC-7269 for targeting the Molluscum contagiosum virus processivity factor (mD4) and demonstrated its ability to inhibit viral processive DNA synthesis in vitro and cellular infection of an mD4-dependent virus (Antiviral Res 211, 2023,105520). However, despite a thorough medicinal chemistry campaign we were unable to generate a potent second analog as a requisite for drug development. We overcame this impasse, by conjugating a short hydrophobic trivaline peptide to FC-7269 to produce FC-TriVal-7269 which significantly increased antiviral potency and reduced cellular toxicity.
Asunto(s)
Antivirales , Virus del Molusco Contagioso , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Virus del Molusco Contagioso/efectos de los fármacos , Humanos , Replicación Viral/efectos de los fármacos , Molusco Contagioso/tratamiento farmacológico , Oligopéptidos/farmacología , Oligopéptidos/química , Animales , Línea CelularAsunto(s)
Administración Tópica , Ácidos Linoleicos/farmacología , Molusco Contagioso/tratamiento farmacológico , Virus del Molusco Contagioso/efectos de los fármacos , Aceites de Plantas/farmacología , Piel/patología , Ácido gammalinolénico/farmacología , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Ácidos Linoleicos/administración & dosificación , Ácidos Linoleicos/uso terapéutico , Masculino , Molusco Contagioso/patología , Molusco Contagioso/virología , Virus del Molusco Contagioso/aislamiento & purificación , Oenothera biennis , Evaluación de Resultado en la Atención de Salud , Aceites de Plantas/administración & dosificación , Aceites de Plantas/uso terapéutico , Piel/virología , Ácido gammalinolénico/administración & dosificación , Ácido gammalinolénico/uso terapéuticoRESUMEN
Biodiversity of the marine world is only partially subjected to detailed scientific scrutiny in comparison to terrestrial life. Life in the marine world depends heavily on marine fungi scavenging the oceans of lifeless plants and animals and entering them into the nutrient cycle by. Approximately 150 to 200 new compounds, including alkaloids, sesquiterpenes, polyketides, and aromatic compounds, are identified from marine fungi annually. In recent years, numerous investigations demonstrated the tremendous potential of marine fungi as a promising source to develop new antivirals against different important viruses, including herpes simplex viruses, the human immunodeficiency virus, and the influenza virus. Various genera of marine fungi such as Aspergillus, Penicillium, Cladosporium, and Fusarium were subjected to compound isolation and antiviral studies, which led to an illustration of the strong antiviral activity of a variety of marine fungi-derived compounds. The present review strives to summarize all available knowledge on active compounds isolated from marine fungi with antiviral activity.
Asunto(s)
Antivirales/aislamiento & purificación , Organismos Acuáticos/química , Hongos/química , Animales , Antivirales/farmacología , VIH/efectos de los fármacos , Humanos , Virus del Molusco Contagioso/efectos de los fármacos , Orthomyxoviridae/efectos de los fármacos , Virus del Síndrome Respiratorio y Reproductivo Porcino/efectos de los fármacos , Virus Sincitiales Respiratorios/efectos de los fármacos , Simplexvirus/efectos de los fármacos , Virus del Mosaico del Tabaco/efectos de los fármacosAsunto(s)
Antibacterianos/uso terapéutico , Manejo de la Enfermedad , Molusco Contagioso/tratamiento farmacológico , Virus del Molusco Contagioso/efectos de los fármacos , Guías de Práctica Clínica como Asunto , Adolescente , Trazado de Contacto , Femenino , Infecciones por VIH/prevención & control , Humanos , Masculino , Virus del Molusco Contagioso/aislamiento & purificación , Salud Reproductiva/normas , Reino UnidoRESUMEN
The dermatological disease molluscum contagiosum (MC) presents as lesions restricted solely to the skin. The poxvirus molluscum contagiosum virus (MCV) is responsible for this skin disease that is easily transmitted through casual contact among all populations, with greater frequency in children and immunosuppressed individuals. In addition, sexual transmission of MCV in adolescents and adults is a health concern. Although the skin lesions ultimately resolve in immunocompetent individuals, they can persist for extended periods, be painful, and result in scarring. Treatment is problematic, and there is no drug that specifically targets MCV. The inability of MCV to propagate in cell culture has impeded drug development. To overcome these barriers, we integrated three new developments. First, we identified a new MCV drug target (mD4) that is essential for processive DNA synthesis in vitro. Second, we discovered a small chemical compound that binds to mD4 and prevents DNA synthesis in vitro. Third, and most significant, we engineered a hybrid vaccinia virus (mD4-VV) in which the natural vaccinia D4 (vD4) gene is replaced by the mD4 target gene. This hybrid virus is dependent on mD4 for viral growth in culture and is inhibited by the small compound. This target system provides, for the first time, a platform and approach for the discovery and evaluation of new therapeutics that can be used to treat MC.
Asunto(s)
ADN Viral , ADN Polimerasa Dirigida por ADN/genética , Virus del Molusco Contagioso/genética , Virus Reordenados/genética , Proteínas Virales/genética , Animales , Antivirales/química , Antivirales/farmacología , Bioensayo , Línea Celular , Chlorocebus aethiops , Clonación Molecular , ADN Polimerasa Dirigida por ADN/metabolismo , Descubrimiento de Drogas , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Células Epiteliales/virología , Expresión Génica , Humanos , Riñón/efectos de los fármacos , Riñón/patología , Riñón/virología , Terapia Molecular Dirigida , Virus del Molusco Contagioso/efectos de los fármacos , Virus del Molusco Contagioso/metabolismo , Plásmidos/química , Plásmidos/metabolismo , Conejos , Virus Reordenados/efectos de los fármacos , Virus Reordenados/metabolismo , Proteínas Recombinantes , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Virus Vaccinia/efectos de los fármacos , Virus Vaccinia/genética , Virus Vaccinia/metabolismo , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/metabolismoRESUMEN
CMX001 (hexadecyloxypropyl-cidofovir, Brincidofovir) is a broad spectrum, lipid conjugate of cidofovir that is converted intracellularly into the active antiviral, cidofovir diphosphate. The lipid conjugation results in oral bioavailability, higher intracellular concentrations of active drug, lower plasma concentrations of cidofovir and increased antiviral potency against dsDNA viruses.
Asunto(s)
Antivirales/uso terapéutico , Citosina/análogos & derivados , Infecciones por Virus ADN/tratamiento farmacológico , Organofosfonatos/uso terapéutico , Adenoviridae/efectos de los fármacos , Antivirales/química , Antivirales/farmacología , Citomegalovirus/efectos de los fármacos , Citosina/química , Citosina/farmacología , Citosina/uso terapéutico , Humanos , Pruebas de Sensibilidad Microbiana , Virus del Molusco Contagioso/efectos de los fármacos , Organofosfonatos/química , Organofosfonatos/farmacología , Orthopoxvirus/efectos de los fármacos , Poliomavirus/efectos de los fármacosRESUMEN
Molluscum contagiosum is a common self-limited viral skin infection. The course of the infection often includes tender, crusted, erythematous lesions that prompt suspicion for bacterial infection. However, these signs of inflammation represent a host response that often precedes resolution of the viral disease, rather than bacterial superinfection, and do not require additional antibacterial treatment. We present a case report and retrospective review of 7 additional cases to characterize the clinical presentation of inflamed molluscum, assess the utilization of medical resources, and consider the psychosocial burden associated with mistaken diagnoses of bacterial infection. We propose the acronym "BOTE"* sign (for beginning of the end) to help underscore the significance of inflammation as an expected variant in the evolution of molluscum immunity.
Asunto(s)
Molusco Contagioso/diagnóstico , Molusco Contagioso/tratamiento farmacológico , Virus del Molusco Contagioso/aislamiento & purificación , Adolescente , Antibacterianos/uso terapéutico , Niño , Preescolar , Fármacos Dermatológicos/uso terapéutico , Servicio de Urgencia en Hospital , Femenino , Estudios de Seguimiento , Humanos , Masculino , Virus del Molusco Contagioso/efectos de los fármacos , Valor Predictivo de las Pruebas , Remisión Espontánea , Medición de Riesgo , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Estados UnidosAsunto(s)
Inmunoglobulina G/efectos adversos , Inmunosupresores/efectos adversos , Molusco Contagioso/inducido químicamente , Virus del Molusco Contagioso/efectos de los fármacos , Infecciones por Papillomavirus/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Etanercept , Femenino , Humanos , Inmunoglobulina G/uso terapéutico , Inmunosupresores/uso terapéutico , Infliximab , Molusco Contagioso/inmunología , Infecciones por Papillomavirus/patología , Psoriasis/tratamiento farmacológico , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Recurrencia , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresAsunto(s)
Antivirales/farmacología , Citosina/análogos & derivados , ADN Polimerasa Dirigida por ADN/metabolismo , Molusco Contagioso/tratamiento farmacológico , Virus del Molusco Contagioso/efectos de los fármacos , Organofosfonatos/farmacología , Cidofovir , Citosina/farmacología , Humanos , Molusco Contagioso/virología , Virus del Molusco Contagioso/genéticaAsunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Aminoquinolinas/uso terapéutico , Molusco Contagioso/tratamiento farmacológico , Administración Tópica , Estudios de Seguimiento , Humanos , Imiquimod , Inmunidad Innata/efectos de los fármacos , Queloide/tratamiento farmacológico , Virus del Molusco Contagioso/efectos de los fármacos , Papillomaviridae/efectos de los fármacos , Infecciones por Papillomavirus/tratamiento farmacológico , Proyectos Piloto , Recurrencia , Verrugas/tratamiento farmacológicoRESUMEN
We have developed microtiter assays for detecting catalysis by type IB topoisomerases and retroviral integrases. Each assay employs model DNA substrates containing biotin in one strand and digoxigenin in another. In each case action of the enzyme results in the formation of a single DNA strand containing both groups. This allows the reaction product to be quantified by capturing biotinylated product DNA on avidin-coated plates followed by detection using an anti-digoxigenin ELISA. The order of addition of reactants and inhibitors can be varied to distinguish effects of test compounds on different steps in the reaction. These assays were used to screen compound libraries for inhibitors active against mammalian topoisomerase or HIV integrase. We identified (-)-epigallocatechin 3-O:-gallate, as a potent inhibitor of religation by mammalian topoisomerase (IC(50) of 26 nM), potentially explaining the anti-cancer properties previously attributed to this compound. New integrase inhibitors were also identified. A similar strategy may be used to develop microtiter assays for many further DNA modifying enzymes.
Asunto(s)
Catequina/análogos & derivados , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/aislamiento & purificación , Integrasa de VIH/metabolismo , VIH-1/enzimología , Virus del Molusco Contagioso/enzimología , Inhibidores de Topoisomerasa I , Animales , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Avidina/metabolismo , Secuencia de Bases , Biotinilación , Catálisis , Catequina/aislamiento & purificación , Catequina/farmacología , ADN-Topoisomerasas de Tipo I/clasificación , ADN-Topoisomerasas de Tipo I/metabolismo , Inhibidores Enzimáticos/farmacología , Ensayo de Inmunoadsorción Enzimática/métodos , Inhibidores de Integrasa VIH/aislamiento & purificación , Inhibidores de Integrasa VIH/farmacología , VIH-1/efectos de los fármacos , Concentración 50 Inhibidora , Virus del Molusco Contagioso/efectos de los fármacos , Reproducibilidad de los Resultados , Factores de TiempoRESUMEN
Molluscum contagiosum virus (MCV) and variola virus (VAR) are the only two poxviruses that are specific for man. MCV causes skin tumors in humans and primarily in children and immunocompromised individuals. MCV is unable to replicate in tissue culture cells or animals. Recently, the DNA sequence of the 190 kbp MCV genome was reported by Senkevich et al. MCV was predicted to encode 163 proteins of which 103 were clearly related to those of smallpox virus. In contrast, it was found that MCV lacks 83 genes of VAR, including those involved in the suppression of the host response to infection, nucleotide biosynthesis, and cell proliferation. However, MCV possesses 59 genes predicted to code for novel proteins including MHC-class I, chemokine and glutathione peroxidase homologs not found in other poxviruses. The MCV genomic data allow the investigation of novel host defense mechanisms and provide new possibilities for the development of therapeutics for treatment and prevention of the MCV infection.