Ribavirin: a drug active against many viruses with multiple effects on virus replication and propagation. Molecular basis of ribavirin resistance

Beaucourt, Stéphanie; Vignuzzi, Marco

doi:10.1016/j.coviro.2014.04.011

Cited by 102 publications

(72 citation statements)

References 49 publications

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“…For example, ribavirin is a guanosine analogue that has a broad‐spectrum activity against many RNA and DNA viruses. Ribavirin has several mechanisms of action (Beaucourt & Vignuzzi, ) including: (a) inhibition of inosine monophosphate dehydrogenase, resulting in depletion of guanosine triphosphate; (b) interfering with mRNA‐capping; (c) stimulating the host immune system to act against the invaded virus; (d) inhibiting viral RNA polymerase; and, (e) enhancing virus mutagenesis (due to the incorporation of ribavirin triphosphate in place of guanosine triphosphate in viral RNA), resulting in viral death.…”

Section: The Need For New Treatmentsmentioning

confidence: 99%

The potential anti‐infective applications of metal oxide nanoparticles: A systematic review

Abo‐zeid

Williams

2019

WIREs Nanomed Nanobiotechnol

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Microbial infections present a major global healthcare challenge, in large part because of the development of microbial resistance to the currently approved antimicrobial drugs. This demands the development of new antimicrobial agents. Metal oxide nanoparticles (MONPs) are a class of materials that have been widely explored for diagnostic and therapeutic purposes. They are reported to have wide‐ranging antimicrobial activities and to be potent against bacteria, viruses, and protozoans. The use of MONPs reduces the possibility of resistance developing because they have multiple mechanisms of action (including via reactive oxygen species generation), simultaneously attacking many sites in the microorganism. However, despite this there are to date no MONPs clinically approved for antimicrobial therapy. This review explores the recent literature in this area, discusses the mechanisms of MONP action against microorganisms, and considers the barriers faced to the use of MONPs in humans. These include biological challenges, of which the potential for an immune response and off‐target toxicity are key. We explore in detail the possible benefits/disbenefits of an immune response being initiated, and consider the effect of production method (chemical vs. green synthesis) on cytotoxicity. There are also a number of technical and manufacturing challenges hindering MONP translation to the clinic which are additionally discussed in depth. In the short term, there are potentially some “quick wins” from the repurposing of already‐approved nanoparticle‐based medicines for anti‐infective applications, but a number of hurdles, both technical and biological, lie in the path to long‐term clinical translation of new MONP‐based formulations. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials

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Section: The Need For New Treatmentsmentioning

confidence: 99%

The potential anti‐infective applications of metal oxide nanoparticles: A systematic review

Abo‐zeid

Williams

2019

WIREs Nanomed Nanobiotechnol

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“…The results of these cell culture-based studies need to be interpreted with caution as the uptake of RBV by several cell lines, including the frequently used African green monkey kidney (Vero) cells, is known to be inefficient (Ibarra and Pfeiffer, 2009;Shah et al, 2010). Furthermore, other mechanisms of virus inhibition by RBV have been reported that do not involve the direct targeting of the virus by incorporation of triphosphorylated RBV into nascent RNA (Beaucourt and Vignuzzi, 2014). Recently it was shown that decreased CoV replication mainly results from inhibition of inosine-5 -monophosphate dehydrogenase (IMPDH) by ribavirin monophosphate and the subsequent lowering of cellular GTP pools (Kim and Lee, 2013;Smith et al, 2014).…”

Section: Inhibitors Of Nidovirus Rna Polymerase Activitymentioning

confidence: 99%

Nidovirus RNA polymerases: Complex enzymes handling exceptional RNA genomes

2017

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Coronaviruses and arteriviruses are distantly related human and animal pathogens that belong to the order Nidovirales. Nidoviruses are characterized by their polycistronic plus-stranded RNA genome, the production of subgenomic mRNAs and the conservation of a specific array of replicase domains, including key RNA-synthesizing enzymes. Coronaviruses (26-34 kilobases) have the largest known RNA genomes and their replication presumably requires a processive RNA-dependent RNA polymerase (RdRp) and enzymatic functions that suppress the consequences of the typically high error rate of viral RdRps. The arteriviruses have significantly smaller genomes and form an intriguing package with the coronaviruses to analyse viral RdRp evolution and function. The RdRp domain of nidoviruses resides in a cleavage product of the replicase polyprotein named non-structural protein (nsp) 12 in coronaviruses and nsp9 in arteriviruses. In all nidoviruses, the C-terminal RdRp domain is linked to a conserved N-terminal domain, which has been coined NiRAN (nidovirus RdRp-associated nucleotidyl transferase). Although no structural information is available, the functional characterization of the nidovirus RdRp and the larger enzyme complex of which it is part, has progressed significantly over the past decade. In coronaviruses several smaller, non-enzymatic nsps were characterized that direct RdRp function, while a 3'-to-5' exoribonuclease activity in nsp14 was implicated in fidelity. In arteriviruses, the nsp1 subunit was found to maintain the balance between genome replication and subgenomic mRNA production. Understanding RdRp behaviour and interactions during RNA synthesis and subsequent processing will be key to rationalising the evolutionary success of nidoviruses and the development of antiviral strategies.

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“…87 Ribavirin has multiple effects on virus replication, such as allowing dNA synthesis to occur, but preventing triphosphate synthesis by inhibiting the enzyme inosine monophosphate dehydrogenase (essential for synthesis of nucleotides); it thus prevents nucleotide production. 87 Systemic application of ribavirin is limited because of side effects. 88 Side effects in cats in several studies (even using low doses) have included haemoly sis, which develops as a result of sequestration of the drug in erythrocytes.…”

Section: Ribavirinmentioning

confidence: 99%