RESUMEN
Human immunodeficiency virus-type 1 (HIV-1) remains one of the leading contributors to the global burden of disease, and novel antiretroviral agents with alternative mechanisms are needed to cure this infection. Here, we describe an exploratory attempt to optimize the antiretroviral properties of benfluron, a cytostatic agent previously reported to exhibit strong anti-HIV activity likely based on inhibitory actions on virus transcription and Rev-mediated viral RNA export. After obtaining six analogs designed to modify the benzo[c]fluorenone system of the parent molecule, we examined their antiretroviral and toxicity properties together with their capacity to recognize the Rev Recognition Element (RRE) of the virus RNA and inhibit the RRE-Rev interaction. The results indicated that both the benzo[c] and cyclopentanone components of benfluron are required for strong RRE-Rev target engagement and antiretroviral activity and revealed the relative impact of these moieties on RRE affinity, RRE-Rev inhibition, antiviral action and cellular toxicity. These data provide insights into the biological properties of the benzo[c]fluorenone scaffold and contribute to facilitating the design of new anti-HIV agents based on the inhibition of Rev function.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , VIH-1/genética , Productos del Gen rev del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen rev del Virus de la Inmunodeficiencia Humana/metabolismo , ARN Viral/genética , Fármacos Anti-VIH/farmacología , Infecciones por VIH/tratamiento farmacológico , Conformación de Ácido NucleicoRESUMEN
Subdomain 5BSL3.2 of hepatitis C virus RNA lies at the core of a network of distal RNA-RNA contacts that connect the 5' and 3' regions of the viral genome and regulate the translation and replication stages of the viral cycle. Using small-angle X-ray scattering and NMR spectroscopy experiments, we have determined at low resolution the structural models of this subdomain and its distal complex with domain 3'X, located at the 3'-terminus of the viral RNA chain. 5BSL3.2 adopts a characteristic 'L' shape in solution, whereas the 5BSL3.2-3'X distal complex forms a highly unusual 'Y'-shaped kissing junction that blocks the dimer linkage sequence of domain 3'X and promotes translation. The structure of this complex may impede an effective association of the viral polymerase with 5BSL3.2 and 3'X to start negative-strand RNA synthesis, contributing to explain the likely mechanism used by these sequences to regulate viral replication and translation. In addition, sequence and shape features of 5BSL3.2 are present in functional RNA motifs of flaviviruses, suggesting conserved regulatory processes within the Flaviviridae family.
Asunto(s)
Flaviviridae , Hepacivirus , Regiones no Traducidas 3' , Genoma Viral , Hepacivirus/genética , Modelos Estructurales , Conformación de Ácido Nucleico , ARN Viral/química , ARN Viral/genética , Replicación Viral/genéticaRESUMEN
INTRODUCTION: Basal cell carcinoma (BCC) is the most common type of non-melanoma malignant skin tumors. Eighty-five percent of all cases are located on the skin of the head and neck. The risk of recurrence after surgery is estimated at 5-15%. AIM: To evaluate the selected risk factors for recurrence after surgical treatment of head and neck BCC at the Department of Head and Neck Surgery in the Greater Poland Cancer Centre of the Poznan University of Medical Sciences. MATERIAL AND METHODS: A retrospective analysis was made of patients treated at the Department of Head and Neck Surgery in the Greater Poland Cancer Centre of the Poznan University of Medical Sciences in 2007-2012 for BCC of the head and neck region. The study covered 312 patients: 198 males (63%) and 114 females (37%), aged 32-96 years. RESULTS: In the study group of 312 tumors, recurrence after initial treatment in this Centre was diagnosed in 18 patients (9%), whereas in patients who were previously operated elsewhere, recurrence was found in 22 cases (17%). The nodular type was the most common BCC type in the study group and concerned 175 patients (56%). The most numerous group (114; 37%) in this study group comprised patients with external nose and cheek tumors. CONCLUSIONS: The importance of preoperative biopsy to assess the histological type as a routine treatment of patients with BCC is essential. Ultrasound evaluation to assess the exact size and depth of tumor invasion should also be implemented.
