Targeting host factors: A novel rationale for the management of hepatitis C virus

Abstract

Hepatitis C is recognized as a major threat to global public health. The current treatment of patients with chronic hepatitis C is the addition of ribavirin to interferon-based therapy which has limited efficacy, poor tolerability, and significant expense. New treatment options that are more potent and less toxic are much needed. Moreover, more effective treatment is an urgent priority for those who relapse or do not respond to current regimens. A major obstacle in combating hepatitis C virus (HCV) infection is that the fidelity of the viral replication machinery is notoriously low, thus enabling the virus to quickly develop mutations that resist compounds targeting viral enzymes. Therefore, an approach targeting the host cofactors, which are indispensable for the propagation of viruses, may be an ideal target for the development of antiviral agents because they have a lower rate of mutation than that of the viral genome, as long as they have no side effects to patients. Drugs targeting, for example, receptors of viral entry, host metabolism or nuclear receptors, which are factors required to complete the HCV life cycle, may be more effective in combating the viral infection. Targeting host cofactors of the HCV life cycle is an attractive concept because it imposes a higher genetic barrier for resistance than direct antiviral compounds. However the principle drawback of this strategy is the greater potential for cellular toxicity.

Fungus-Derived Neoechinulin B as a Novel Antagonist of Liver X Receptor, Identified by Chemical Genetics Using a Hepatitis C Virus Cell Culture System

“…HCV RNA replication is regulated by numerous cellular factors and environments (6,7,45). To identify the target molecules of NeoB, we performed a transcriptome analysis that compared cellular gene expression between NeoB-treated and untreated Huh-7.5.1 cells.…”

“…Second, the use of different virus cell culture systems permits the determination of the step(s) in the viral life cycle that is targeted by novel bioactivities (6). Third, the targets of bioactive compounds can be readily identified using the information of a panel of cellular factors known to be involved in viral replication (5,7). In the present study, we used the hepatitis C virus cell culture (HCVcc) system to identify the bioactivity and target molecule of a fungus-derived natural product known as neoechinulin B (NeoB).…”

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

“…In addition, many organisms, especially viruses, generate a platform for the reproduction of the organism and then get released from the cell interior (38). Identification of host proteins that these pathogens require at any point of their life cycle is an important goal that may uncover new therapeutic opportunities (777,1239). Phosphoinositides, again, are important regulators of many of these processes.…”

Inhibition of Enveloped Virus Infection of Cultured Cells by Valproic Acid

“…One of the approaches to circumvent this limitation is the identification of antivirals targeted against cellular functions required for the virus to complete its viral cycle, thus reducing the potential of viruses to escape from drug effects (26,35,44). Indeed, some long-used drugs commonly administered by clinicians to treat human disorders, such as lithium or statins, have been proposed as new antiviral agent candidates (3,18,20) as part of drug repositioning (finding of new applications to licensed drugs) in drug development.…”