Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “antiviral development”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 163 records · Page 9Linked to original sources

Translational control of viral gene expression in eukaryotes.

As obligate intracellular parasites, viruses rely exclusively on the translational machinery of the host cell for the synthesis of viral proteins. This relationship has imposed numerous challenges on both the infecting virus and the host cell. Importantly, viruses must compete with the endogenous transcripts of the host cell for the translation of viral mRNA. Eukaryotic viruses have thus evolved diverse mechanisms to ensure translational efficiency of viral mRNA above and beyond that of cellular mRNA. Mechanisms that facilitate the efficient and selective translation of viral mRNA may be inherent in the structure of the viral nucleic acid itself and can involve the recruitment and/or modification of specific host factors. These processes serve to redirect the translation apparatus to favor viral transcripts, and they often come at the expense of the host cell. Accordingly, eukaryotic cells have developed antiviral countermeasures to target the translational machinery and disrupt protein synthesis during the course of virus infection. Not to be outdone, many viruses have answered these countermeasures with their own mechanisms to disrupt cellular antiviral pathways, thereby ensuring the uncompromised translation of virion proteins. Here we review the varied and complex translational programs employed by eukaryotic viruses. We discuss how these translational strategies have been incorporated into the virus life cycle and examine how such programming contributes to the pathogenesis of the host cell.

3' Untranslated Regions↗

SARS virus: the beginning of the unraveling of a new coronavirus.

Severe acute respiratory syndrome (SARS) virus caused a severe outbreak in several regions of the world in 2003. The virus is a novel coronavirus, which may have an origin in wild animals such as civet cats in southern China. Its genome structure, gene expression pattern and protein profiles are similar to those of other coronaviruses. However, distinct patterns of several open reading frames in the SARS virus genome may contribute to its severe virulence. The potential mutability of the coronavirus genome may pose problems in the control of future SARS outbreaks. The mechanism of SARS pathogenesis may involve both direct viral cytocidal effects on the target cells and immune-mediated mechanisms. The life cycle of the SARS virus is largely unknown; however, based on the analogy with other coronaviruses, several potential targets for antiviral development are identified. Vaccines offer an important preventive measure for possible future recurrences of SARS, but the prospect for their development is still unknown because of the uncertainty regarding the role of immune responses in SARS virus pathogenesis. The comparative studies of other coronaviruses offer insights into the understanding of SARS virus.

Chromosome Mapping↗

Rab10 coordinates SADS-CoV non-lytic egress through the ERGIC-TGN-lysosome trafficking pathway.

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a bat-originated alphacoronavirus that causes devastating enteric disease in neonatal piglets and possesses significant potential for cross-species transmission. While the early stages of the coronavirus life cycle have been extensively characterized, the host factors indispensable for virion assembly and subsequent export remain largely enigmatic. Here, by performing a genome-wide CRISPR-Cas9 knockout screen using a recombinant icSADS-CoV-GFP reporter virus, we identified the small GTPase Rab10 as a critical host dependency factor for SADS-CoV infection. Viral life cycle analysis revealed that Rab10 is not required for viral attachment, entry, or initial genome replication, but is essential for the virion transport and non-lytic egress. Rab10 deficiency markedly reduced the extracellular release of viral RNA, viral proteins, and infectious progeny, as well as the secretion of SADS-CoV virus-like particles. Confocal imaging showed that Rab10 and viral protein-positive intracellular structures were associated with LMAN1, TGN46, and LAMP1 positive compartments. These findings support a model in which Rab10 coordinates a virus-containing vesicles trafficking pathway associated with ERGIC-TGN-lysosome compartments. Mechanistically, Rab10 facilitates the loading of the viral envelope (E) protein into transport vesicles derived from the ERGIC. Rab10 associates with the SADS-CoV E protein, and mapping analyses implicated the C-terminal PDZ-binding motif, particularly residue V75, in efficient Rab10 association and viral release. Collectively, our findings identify Rab10 as a host regulator of SADS-CoV non-lytic egress and highlight the E-Rab10 interaction and the vesicular trafficking machinery as a potential target for developing antiviral strategies.

Animals↗

Molecular diagnostics in an insecure world.

As of October 2001, the potential for use of infectious agents, such as anthrax, as weapons has been firmly established. It has been suggested that attacks on a nations' agriculture might be a preferred form of terrorism or economic disruption that would not have the attendant stigma of infecting and causing disease in humans. Highly pathogenic avian influenza virus is on every top ten list available for potential agricultural bioweapon agents, generally following foot and mouth disease virus and Newcastle disease virus at or near the top of the list. Rapid detection techniques for bioweapon agents are a critical need for the first-responder community, on a par with vaccine and antiviral development in preventing spread of disease. There are several current approaches for rapid, early responder detection of biological agents including influenza A viruses. There are also several proposed novel approaches in development. The most promising existing approach is real-time fluorescent PCR analysis in a portable format using exquisitely sensitive and specific primers and probes. The potential for reliable and rapid early-responder detection approaches are described, as well as the most promising platforms for using real-time PCR for avian influenza, as well as other potential bioweapon agents.

Animals↗

SARS: understanding the virus and development of rational therapy.

In late 2002 a new disease, severe atypical respiratory syndrome (SARS), emerged in China. A hitherto unknown animal coronavirus (CoV) that had crossed the species barrier through close contact of humans with infected animals was identified as the etiological agent. It rapidly adapted to the new host and not only became readily transmissible between humans but also more pathogenic. Air travel spread it rapidly around the world and ultimately the virus infected 8096 people and caused 774 deaths in 26 countries on 5 continents. Aggressive quarantine measures successfully terminated the disease. Currently, there are no SARS cases recorded and most likely the virus no longer circulates in the human population. In this review we present an overview over SARS-Co virus biology, the disease and discuss strategies to develop antiviral drugs and vaccines.

Animals↗

Screening for PreS specific binding ligands with a phage displayed peptides library.

AIM: To construct a random peptide phage display library and search for peptides that specifically bind to the PreS region of hepatitis B virus (HBV). METHODS: A phage display vector, pFuse8, based on the gene 8 product (pVIII) of M13 phage was made and used to construct a random peptide library. E.coli derived thioredoxin-PreS was purified with Thio-bond beads, and exploited as the bait protein for library screening. Five rounds of bio-panning were performed. The PreS-binding specificities of enriched phages were characterized with phage ELISA assay. RESULTS: A phage display vector was successfully constructed as demonstrated to present a pVIII fused HBV PreS1 epitope on the phage surface with a high efficiency. A cysteine confined random peptide library was constructed containing independent clones exceeding 5+/-10(8) clone forming unit (CFU). A pool of phages showing a PreS-binding specificity was obtained after the screening against thio-PreS with an enrichment of approximately 400 times. Five phages with high PreS-binding specificities were selected and characterized. Sequences of the peptides displayed on these phages were determined. CONCLUSION: A phage library has been constructed, with random peptides displaying as pVIII-fusion proteins. Specific PreS-binding peptides have been obtained, which may be useful for developing antivirals against HBV infection.

Amino Acid Sequence↗

[Practical evaluation of rapid diagnostic tests for mycobacteriosis and virus infection].

Because cultures of mycobacteria and viruses take a great number of days, the results are delayed in these clinical laboratory tests. For this reason, rapid diagnostic tests without these cultures are required. Among the laboratory tests of mycobacteria, acid-fast stain as a rapid diagnostic test is the first to give significant information to laboratory staffs and physicians. There are mainly two procedures, directly smearing clinical specimens and smearing concentrated specimens treated with NALC-NaOH on slide glass. The former is performed for specimens from emergency patients. When a patient is suspected of tuberculosis, a DNA-amplification test such as COBAS AMPLICOR TEST (PCR test) is performed for directly detecting Mycobacterium tuberculosis in clinical specimens, regardless of whether the specimens show positive or negative by acid-fast stain. Sixty-one of 1,023 specimens tested in Showa University Fujigaoka Hospital in February 2000-May 2002 were found positive by both PCR and culture tests. Fourteen were found negative by PCR test and positive by culture test. Five were found positive by PCR test and negative by culture test. Alternatively, MTB-64 (Capilia TB) is a kit for rapidly identifying M. tuberculosis using colonies. The time necessary for completion of the test was approximately 15 minutes per sample. In our study, the identification test showed weak-positive for 2 strains of M. marinum (ATCC927 and one clinical isolate), compared with positive for 28 clinical isolates and strain H37Ra of M. tuberculosis. Recently, rapid diagnostic kits for detecting various pathogenic viruses have been developed. The kits for detecting influenza virus are in especially great demand with the spread of newly-developed antiviral agents. There was an epidemic of the type A virus in the winters 2001-2002. 101 (32%) of 316 clinical specimens tested in the hospital were found positive with InfluA. B-Quick [SEIKEN] (Denka) or Directigen Flu A (Becton Dickinson). These kits showed high utility. Also, Abbot TESTPACK RSV (Dainabot) for detecting RS virus and ROTALEX DRY (Orion Diagnostica) for detecting rotavirus showed high utility. However, these rapid diagnostic kits have weak points: high costs, false positives and false negatives. Thus, more improvements are required.

Bacteriological Techniques↗

Inhibition of respiratory syncytial virus by RhoA-derived peptides: implications for the development of improved antiviral agents targeting heparin-binding viruses.

The respiratory syncytial virus (RSV) fusion glycoprotein (F) can interact with the small intracellular GTPase RhoA, and peptides derived from RhoA inhibit RSV replication. These observations initially suggested that RhoA-derived peptides might inhibit RSV replication by disrupting an in vivo interaction between RSV F and RhoA. However, recent data indicate that the antiviral activity of RhoA-derived peptides is not due to competitive inhibition of an hypothesized F-RhoA interaction, but is rather a function of the peptides' intrinsic biophysical properties. We summarize here what is known about the mechanism of RSV inhibition by these peptides and give our opinion regarding the potential implications of this work with regards to RSV biology, and to the development of antiviral agents targeting RSV and other enveloped viruses.

Antiviral Agents↗

Developments in the antiviral treatment of genital herpes.

There have been impressive advances made over the last decade in the management of sexually transmitted viral diseases, especially in the development of effective antiviral agents. Acyclovir, first synthesized in 1974, has proved to be an effective and safe drug for the treatment of primary and frequently recurring genital herpes, according to the various medical publications over the last 10 years. This article reviews the use of acyclovir in the treatment of genital herpes and discusses the potential problem of acyclovir resistance. It also discusses two newer antiherpes drugs, famciclovir and valaciclovir, and the preliminary results of studies on their efficacy in the treatment of genital herpes.

2-Aminopurine↗

Interferon-induced proteins in human fibroblasts and development of the antiviral state.

Treatment of human fibroblasts with interferon induces the synthesis of several proteins, as detected by incorporation of [35S]methionine followed by analysis of cell extracts by polyacrylamide gel electrophoresis. The induction of these proteins had features in common with the development of the antiviral effect of interferon, such as (i) sensitivity to actinomycin D and cycloheximide when these compounds were added together with interferon, (ii) insensitivity to actinomycin D if the actinomycin D was added 2 h after the addition of interferon, (iii) similar dependence on interferon concentration, and (iv) species specificity for interferon. When interferon treatment was given in the presence of cycloheximide and actinomycin D was added before the removal of cycloheximide, all four proteins were induced, thus suggesting that their inductions are coordinated. Labeling for 2-h periods at varying time intervals after the addition of interferon revealed that the synthesis of these proteins was induced within a few hours, peaked at different time intervals, and was soon followed by a marked decline, suggesting that the mRNA's for these proteins have short half-lives. Moreover, this decline occurred despite the fact that the cells were continuously exposed to interferon, and there was no measurable loss of interferon activity in the medium. This suggests that the induction of these proteins is transient and is apparently subject to further control.

Cell Line↗

Recent highlights in the development of new antiviral drugs.

Twenty antiviral drugs, that is about half of those that are currently approved, are formally licensed for clinical use in the treatment of human immunodeficiency virus infections (acquired immune deficiency syndrome). The others are used in the treatment of herpesvirus (e.g. herpes simplex virus, varicella zoster virus and cytomegalo virus), hepatitis B virus, hepatitis C virus or influenza virus infections. Recent endeavours have focussed on the development of improved antiviral therapies for virus infections that have already proved amenable to antiviral drug treatment, as well as for virus infections for which, at present, no antiviral drugs have been formally approved (i.e. human papilloma viruses, adenoviruses, human herpesvirus type 6, poxviruses, severe acute respiratory syndrome coronavirus and hemorrhagic fever viruses).

Animals↗

Activation of TBK1 and IKKvarepsilon kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunity.

Mounting an immune response to a viral pathogen involves the initial recognition of viral antigens through Toll-like receptor-dependent and -independent pathways and the subsequent triggering of signal transduction cascades. Among the many cellular kinases stimulated in response to virus infection, the noncanonical IKK-related kinases TBK1 and IKKepsilon have been shown to phosphorylate and activate interferon regulatory factor 3 (IRF-3) and IRF-7, leading to the production of alpha/beta interferons and the development of a cellular antiviral state. In the present study, we examine the activation of TBK1 and IKKepsilon kinases by vesicular stomatitis virus (VSV) infection in human lung epithelial A549 cells. We demonstrate that replication-competent VSV is required to induce activation of the IKK-related kinases and provide evidence that ribonucleoprotein (RNP) complex of VSV generated intracellularly during virus replication can activate TBK1 and IKKepsilon activity. In TBK1-deficient cells, IRF-3 and IRF-7 activation is significantly reduced, although transcriptional upregulation of IKKepsilon following treatment with VSV, double-stranded RNA, or RNP partially compensates for the loss of TBK1. Biochemical analyses with purified TBK1 and IKKepsilon kinases in vitro demonstrate that the two kinases exhibit similar specificities with respect to IRF-3 and IRF-7 substrates and both kinases target serine residues that are important for full transcriptional activation of IRF-3 and IRF-7. These data suggest that intracellular RNP formation contributes to the early recognition of VSV infection, activates the catalytic activity of TBK1, and induces transcriptional upregulation of IKKepsilon in epithelial cells. Induction of IKKepsilon potentially functions as a component of the amplification mechanism involved in the establishment of the antiviral state.

Cell Line, Tumor↗

Perspectives on the development of acyclic nucleotide analogs as antiviral drugs.

The development of Viread (tenofovir disoproxil) for HIV and Hepsera (adefovir dipivoxil) for HBV presented many unique challenges. Unlike nucleosides and most conventional drugs, the parent acyclic nucleotide analogs are charged at physiologic pH and not suitable for oral administration which is highly desired in chronic therapies. Physicochemical properties, cellular permeation, renal toxicity, and bioavailability all had to be addressed during the development of these compounds. As a class, the acyclic nucleotides have long intracellular half-lives, allowing once-daily dosing, which provided the initial rationale for treatment of chronic viral diseases such as HIV and HBV. Prodrugs originally designed to deliver the parent acyclic nucleotide analog to the systemic circulation, also function to increase the tissue distribution and intracellular concentrations of the acyclic nucleotide diphosphate inside cells.

Adenine↗

Treatment with meliacine, a plant derived antiviral, prevents the development of herpetic stromal keratitis in mice.

Herpetic stromal keratitis is caused by ocular infection with herpes simplex virus type 1 (HSV-1) and constitutes a leading cause of human blindness. The effect of meliacine, an antiviral compound isolated from leaves of Melia azedarach L. that inhibits HSV-1 replication in vitro, was examined on experimental corneal HSV-1 inoculation in Balb/c mice. Mice were inoculated with HSV-1 strain KOS at their corneas after abrasion. Meliacine was administered topically 3 times a day for 4 days beginning 1 day before inoculation. Infected animals treated or not with meliacine were observed carefully for the development of stromal keratitis and the clinical scoring was done 14 days post-infection. Histological examination of corneas and viral isolation from eyes from HSV-1 infected mice treated or not with meliacine were also carried out. It was found that the treatment of HSV-1-induced ocular disease in Balb/c mice with meliacine reduced significantly the development of clinical disease, as well as the histological damage in corneas. The viral titers detected in eyes of infected and treated mice were 2-orders-of-magnitude lower than those corresponding to HSV-1 infected control animals. Mock-infected and treated mice did not reveal any corneal alteration due to the administration of the compound. Meliacine was found to exert a strong antiviral action on HSV-1-induced ocular disease in mice with no evidence of toxic effects.

Animals↗

Severe acute respiratory syndrome coronavirus infection of mice transgenic for the human Angiotensin-converting enzyme 2 virus receptor.

Animal models for severe acute respiratory syndrome (SARS) coronavirus infection of humans are needed to elucidate SARS pathogenesis and develop vaccines and antivirals. We developed transgenic mice expressing human angiotensin-converting enzyme 2, a functional receptor for the virus, under the regulation of a global promoter. A transgenic lineage, designated AC70, was among the best characterized against SARS coronavirus infection, showing weight loss and other clinical manifestations before reaching 100% mortality within 8 days after intranasal infection. High virus titers were detected in the lungs and brains of transgene-positive (Tg+) mice on days 1 and 3 after infection. Inflammatory mediators were also detected in these tissues, coinciding with high levels of virus replication. Lower virus titers were also detected in other tissues, including blood. In contrast, infected transgene-negative (Tg-) mice survived without showing any clinical illness. Pathologic examination suggests that the extensive involvement of the central nervous system likely contributed to the death of Tg+ mice, even though viral pneumonia was present. Preliminary studies with mice of a second lineage, AC63, in which the transgene expression was considerably less abundant than that in the AC70 line, revealed that virus replication was largely restricted to the lungs but not the brain. Importantly, despite significant weight loss, infected Tg+ AC63 mice eventually recovered from the illness without any mortality. The severity of the disease that developed in these transgenic mice--AC70 in particular--makes these mouse models valuable not only for evaluating the efficacy of antivirals and vaccines, but also for studying SARS coronavirus pathogenesis.

Animals↗

[Mechanisms of the effect of antiviral agents].

This article reviews diverse strategies of rational development of antivirals based upon an interference with processes involved in viral multiplication cycle. With the aid of approved antiviral drugs as well as of antiviral drugs candidates in diverse stages of development this review demonstrates broad variability of chemical structure and mechanism of action in the field of antiviral development.

Antiviral Agents↗

Antiviral drugs in development for herpes zoster.

Until recently aciclovir has been the only licensed drug for the treatment of herpes zoster. A number of new drugs have emerged over the past few years which offered the potential for improved efficacy or ease of administration. With the completion of the first efficacy trials for each of these agents it has become apparent that, whilst less frequent dosing can he accomplished, it is not easy to significantly improve on the efficacy of aciclovir. Increasing age, the presence of prodromal pain and more severe pain at presentation have, however, been found to predispose to a longer duration of pain. Taking cessation of pain as the single most important parameter, at least for the older immunocompetent population as a whole, only valaciclovir has, to date, been shown to be superior to standard therapy with aciclovir. This review utilises primarily intent-to-treat data to illustrate the relative efficacy of the different therapies.

2-Aminopurine↗

Novel agents and strategies to treat herpes simplex virus infections.

The quiet pandemic of herpes simplex virus (HSV) infection has plagued humanity since ancient times, causing mucocutaneous infection, such as herpes labialis and herpes genitalis. Disease symptoms often interfere with everyday activities and occasionally HSV infections are the cause of life-threatening or sight-impairing disease, especially in neonates and the immunocompromised patient population. After primary or initial infection the virus persists for life in a latent form in neurons of the host, periodically reactivating and often resulting in significant psychosocial distress for the patient. Currently, no cure is available. In the mid-1950s the first antiviral, idoxuridine, was developed for topical treatment of herpes disease and, in 1978, vidarabine was licensed for systemic use to treat HSV encephalitis. Acyclovir (Zovirax), a potent, specific and tolerable nucleosidic inhibitor of the herpes DNA polymerase, was a milestone in the development of antiviral drugs in the late 1970s. In the mid-1990s, when acyclovir became a generic drug, valacyclovir (Valtrex) and famciclovir (Famvir), prodrugs of the gold standard and penciclovir (Denavir), Vectavir), a close analogue, were launched. Though numerous approaches and strategies were tested and considerable effort was expended in the search of the next generation of an antiherpetic therapy, it proved difficult to outperform acyclovir. Notable in this regard was the award of a Nobel Prize in 1988 for the elucidation of mechanistic principles which resulted in the development of new drugs such as acyclovir. Vaccines, interleukins, interferons, therapeutic proteins, antibodies, immunomodulators and small-molecule drugs with specific or nonspecific modes of action lacked either efficacy or the required safety profile to replace the nucleosidic drugs acyclovir, valacyclovir, penciclovir and famciclovir as the first choice of treatment. Recently though, new inhibitors of the HSV helicase-primase with potent in vitro antiherpes activity, novel mechanisms of action, low resistance rates and superior efficacy against HSV in animal models have been discovered. This review summarises the current therapeutic options, discusses the potential of preclinical or investigational drugs and provides an up-to-date interpretation of the challenge to establish novel treatments for herpes simplex disease.

Animals↗