Sequence determinants of 3A-mediated resistance to enviroxime in rhinoviruses and enteroviruses

Heinz, Beverly A.; Vance, L M

doi:10.1128/jvi.70.7.4854-4857.1996

Cited by 53 publications

(21 citation statements)

References 16 publications

(18 reference statements)

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“…Interestingly, a single point mutation in the viral protein 3A can bypass the need of CVB3 for PI4KIIIβ without affecting its virulence (Thibaut et al, 2014;van der Schaar et al, 2012). This mutation has been identified earlier as resistance mutation against enviroxime, a small molecule drug inhibiting replication of different positive-strand RNA viruses like PV, CVB3 and rhinoviruses (Heinz and Vance, 1996). However, it also confers cross-resistance to other inhibitors like PIK93, which efficiently targets PI4KIIIβ (Borawski et al, 2009), or to direct knockdown of PI4KIIIβ.…”

Section: Lipid-modifying Enzymes and Transportersmentioning

confidence: 99%

Ultrastructure of the replication sites of positive-strand RNA viruses

2015

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Positive strand RNA viruses replicate in the cytoplasm of infected cells and induce intracellular membranous compartments harboring the sites of viral RNA synthesis. These replication factories are supposed to concentrate the components of the replicase and to shield replication intermediates from the host cell innate immune defense. Virus induced membrane alterations are often generated in coordination with host factors and can be grouped into different morphotypes. Recent advances in conventional and electron microscopy have contributed greatly to our understanding of their biogenesis, but still many questions remain how viral proteins capture membranes and subvert host factors for their need. In this review, we will discuss different representatives of positive strand RNA viruses and their ways of hijacking cellular membranes to establish replication complexes. We will further focus on host cell factors that are critically involved in formation of these membranes and how they contribute to viral replication.

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Section: Lipid-modifying Enzymes and Transportersmentioning

confidence: 99%

Ultrastructure of the replication sites of positive-strand RNA viruses

2015

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“…The amino acid differences responsible for the rhodanine-resistant phenotype have not yet been identified. Similarly, resistance to enviroxime, an inhibitor of picornavirus RNA replication, has been mapped to the 3A protein, and amino acid substitutions conferring resistance have been mapped for human rhinovirus 14, PV 1 (158), and CBV 3 (159). If clinically useful antiviral agents were identified, it would be necessary to monitor drug resistance.…”

Section: Determination Of Sensitivity or Resistancementioning

confidence: 99%

Molecular Typing of Enteroviruses: Current Status and Future Requirements

et al. 1998

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Human enteroviruses have traditionally been typed according to neutralization serotype. This procedure is limited by the difficulty in culturing some enteroviruses, the availability of antisera for serotyping, and the cost and technical complexity of serotyping procedures. Furthermore, the impact of information derived from enterovirus serotyping is generally perceived to be low. Enteroviruses are now increasingly being detected by PCR rather than by culture. Classical typing methods will therefore no longer be possible in most instances. An alternative means of enterovirus typing, employing PCR in conjunction with molecular genetic techniques such as nucleotide sequencing or nucleic acid hybridization, would complement molecular diagnosis, may overcome some of the problems associated with serotyping, and would provide additional information regarding the epidemiology and biological properties of enteroviruses. We argue the case for developing a molecular typing system, discuss the genetic basis of such a system, review the literature describing attempts to identify or classify enteroviruses by molecular methods, and suggest ways in which the goal of molecular typing may be realized.

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“…Surprisingly, no shift in antiviral potency was seen in the comparison of wild-type viruses to mutant viruses in the regular HRV CPE-based assay. Published data suggested that the mutations that seemed to confer resistance to enviroxime did not confer a very high resistance level (41). In order to assess the resistance potency of the mutation, a different approach was taken.…”

Section: Screening Of a Diverse Subset Of The Proprietary Collection mentioning

confidence: 99%

Phosphatidylinositol 4-Kinase III Beta Is Essential for Replication of Human Rhinovirus and Its Inhibition Causes a Lethal Phenotype In Vivo

Spickler

Lippens

Laberge

et al. 2013

Antimicrob Agents Chemother

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Human rhinovirus (HRV) is the predominant cause of the common cold, but more importantly, infection may have serious repercussions in asthmatics and chronic obstructive pulmonary disorder (COPD) patients. A cell-based antiviral screen against HRV was performed with a subset of our proprietary compound collection, and an aminothiazole series with pan-HRV species and enteroviral activity was identified. The series was found to act at the level of replication in the HRV infectious cycle. In vitro selection and sequencing of aminothiazole series-resistant HRV variants revealed a single-nucleotide mutation leading to the amino acid change I42V in the essential HRV 3A protein. This same mutation has been previously implicated in resistance to enviroxime, a former clinical-stage antipicornavirus agent. Enviroxime-like compounds have recently been shown to target the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIII␤). A good correlation between PI4KIII␤ activity and HRV antiviral potency was found when analyzing the data over 80 compounds of the aminothiazole series, covering a 750-fold potency range. The mechanism of action through PI4KIII␤ inhibition was further demonstrated by small interfering RNA (siRNA) knockdown of PI4KB, which reduced HRV replication and also increased the potency of the PI4KIII␤ inhibitors. Inhibitors from two different structural classes with promising pharmacokinetic profiles and with very good selectivity for PI4KIII␤ were used to dissociate compound-related toxicity from target-related toxicity. Mortality was seen in all dosing groups of mice treated with either compound, therefore suggesting that short-term inhibition of PI4KIII␤ is deleterious.

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Sequence determinants of 3A-mediated resistance to enviroxime in rhinoviruses and enteroviruses

Cited by 53 publications

References 16 publications

Ultrastructure of the replication sites of positive-strand RNA viruses

Ultrastructure of the replication sites of positive-strand RNA viruses

Molecular Typing of Enteroviruses: Current Status and Future Requirements

Phosphatidylinositol 4-Kinase III Beta Is Essential for Replication of Human Rhinovirus and Its Inhibition Causes a Lethal Phenotype In Vivo

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