4 research outputs found
Are statins a viable option for the treatment of infections with the hepatitis C virus?
Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are widely used for the treatment of hypercholesterolemia. Besides their cholesterol-lowering effect, statins have been reported to have antiviral activity against a variety of viruses, including hepatitis C virus (HCV). Several statins inhibit the in vitro replication of subgenomic HCV replicons and also suppress in vitro RNA replication of infectious HCV. The precise mechanism of the anti-HCV activity of statins has not yet been defined. Recent studies suggest that the antiviral effect may result from the inhibition of geranylgeranylation of cellular proteins, rather than the inhibition of cholesterol synthesis. Despite the antiviral effect observed in vitro, statin monotherapy seems to be insufficient for the treatment of chronic HCV infection. However, several prospective and retrospective studies have demonstrated that the addition of statins to IFN-α and ribavirin therapy increases SVR, RVR, and EVR rates without the occurrence of additional adverse events. These clinical data, together with the excellent safety profile and low cost, suggest that statins may play a role in HCV therapy until more potent and safe direct-acting antivirals become available. This article forms part of a symposium in Antiviral Research on “Hepatitis C: next steps toward global eradication.publisher: Elsevier
articletitle: Are statins a viable option for the treatment of infections with the hepatitis C virus?
journaltitle: Antiviral Research
articlelink: http://dx.doi.org/10.1016/j.antiviral.2014.02.020
content_type: simple-article
copyright: Copyright © 2014 Published by Elsevier B.V.status: publishe
Understanding the molecular mechanism of host-based statin resistance in hepatitis C virus replicon containing cells
A number of statins, the cholesterol-lowering drugs, inhibit the in vitro replication of hepatitis C virus (HCV). In HCV-infected patients, addition of statins to the earlier standard of care therapy (pegIFN-α and ribavirin) resulted in increased sustained virological response rates. The mechanism by which statins inhibit HCV replication has not yet been elucidated. In an attempt to gain insight in the underlying mechanism, hepatoma cells carrying an HCV replicon were passaged in the presence of increasing concentrations of fluvastatin. Fluvastatin-resistant replicon containing cells could be generated and proved ∼8-fold less susceptible to fluvastatin than wild-type cultures. The growth efficiency of the resistant replicon containing cells was comparable to that of wild-type replicon cells. The fluvastatin-resistant phenotype was not conferred by mutations in the viral genome but is caused by cellular changes. The resistant cell line had a markedly increased HMG-CoA reductase expression upon statin treatment. Furthermore, the expression of the efflux transporter P-gp was increased in fluvastatin-resistant replicon cells (determined by qRT-PCR and flow cytometry). This increased expression resulted also in an increased functional transport activity as measured by the P-gp mediated efflux of calcein AM. In conclusion, we demonstrate that statin resistance in HCV replicon containing hepatoma cells is conferred by changes in the cellular environment.publisher: Elsevier
articletitle: Understanding the molecular mechanism of host-based statin resistance in hepatitis C virus replicon containing cells
journaltitle: Biochemical Pharmacology
articlelink: http://dx.doi.org/10.1016/j.bcp.2015.06.003
content_type: article
copyright: Copyright © 2015 Elsevier Inc. All rights reserved.status: publishe
Building a Molecular Trap for a Serine Protease from Aptamer and Peptide Modules
In drug development, molecular intervention
strategies are usually
based on interference with a single protein function, such as enzyme
activity or receptor binding. However, in many cases, protein drug
targets are multifunctional, with several molecular functions contributing
to their pathophysiological actions. Aptamers and peptides are interesting
synthetic building blocks for the design of multivalent molecules
capable of modulating multiple functions of a target protein. Here,
we report a molecular trap with the ability to interfere with the
activation, catalytic activity, receptor binding, etc. of the serine
protease urokinase-type plasminogen activator (uPA) by a rational
combination of two RNA aptamers and a peptide with different inhibitory
properties. The assembly of these artificial inhibitors into one molecule
enhanced the inhibitory activity between 10- and 10,000-fold toward
several functions of uPA. The study highlights the potential of multivalent
designs and illustrates how they can easily be constructed from aptamers
and peptides using nucleic acid engineering, chemical synthesis, and
bioconjugation chemistry. By aptamer to aptamer and aptamer to peptide
conjugation, we created, to the best of our knowledge, the first trivalent
molecule which combines three artificial inhibitors binding to three
different sites in a protein target. We hypothesize that by simultaneously
preventing all of the functional interactions and activities of the
target protein, this approach may represent an alternative to siRNA
technology for a functional knockout