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At least 1,261 records · Page 70Linked to original sources
PubMed2003

A system of protein target sequences for anti-RNA-viral chemotherapy by a vitamin B6-derived zinc-chelating trioxa-adamantane-triol.

The synthesis of the structurally unusual heterotricyclic compound 1-[3-hydroxy-5-(hydroxymethyl)-2-methyl-4-pyridinyl]-2,8,9-trioxaadamantane-3,5,7-triol (trivially named bananin, BN) from pyridoxylidenephloroglucinol and a theoretical prospect on possible biological activities of BN are presented in this report. Pyridoxylidenephloroglucinol is synthesized by Knoevenagel condensation of the vitamin B6 aldehyde pyridoxal with phloroglucinol. Pyridoxylidenephloroglucinol rearranges to light-yellow (4'RS)-1',4'-dihydrobananin by refluxing in 5M hydrochloric acid. Air oxidation subsequently forms BN in the heat which immediately yields orange-yellow (4'RS)-4'-chloro-1',4'-dihydrobananin by 1,4-addition of hydrogen chloride. This intermediate could be isolated but, interestingly, not a BN hydrochloride. Brown BN is finally achieved by base-catalyzed elimination of hydrogen chloride from (4'RS)-4'-chloro-1',4'-dihydrobananin. Regarding possible biological activities, it was demonstrated that BN acts as zinc (Zn2+) chelator. Therefore, a target of interest could be the human immunodeficiency virus type 1 (HIV-1) zinc finger HIV-1 RNA-binding nucleocapsid protein p7 (NCp7). Through suggested zinc ejection from HIV-1 genomic RNA psi-element-binding and HIV-1-RNA-duplex packaging NCp7 by BN, thus rendering NCp7 functionally obsolete, it is deduced that HIV-1 replication and effective infectious virion encapsidation could be inhibited by BN. Furthermore, theoretical and structural considerations propose that BN is converted into bananin 5'-monophosphate (BNP) by the cell type-ubiquitous human enzyme pyridoxal kinase (EC 2.7.1.35). Together with the putative antilentiviral retinoid vitamin A-vitamin B6 conjugate analogue B6RA (Kesel, A. J. Biochem. Biophys. Res. Comm. 2003, 300, 793), BNP is postulated to serve as effector in a system of protein target sequences RX(D/E) of RNA virus components. Human immunodeficiency Retroviridae (HIVs) could possibly be influenced by B6RA and BNP. In addition, candidate targets of B6RA and BNP could be adsorption, transcription and/or viral RNA replication of an interestingly wide RNA virus selection including Picornaviridae (poliovirus, human coxsackievirus, hepatitis A virus), Flaviviridae (yellow fever virus, Dengue virus, West Nile virus, Kunjin virus, St. Louis encephalitis virus, hepatitis C virus), Togaviridae (rubella virus), Coronaviridae (human coronavirus, human SARS-associated coronavirus), Rhabdoviridae (rabies virus), Paramyxoviridae (human parainfluenza virus, measles virus, human respiratory syncytial virus), Filoviridae (Marburg virus, Ebola virus), Bornaviridae (Borna disease virus), Bunyaviridae (Hantaan virus), Arenaviridae (Lassa virus), and Reoviridae (human rotavirus). The postulated scope of 'metabolically trapped' BNP might resemble the antiviral spectrum of the RNA-viral virustatic ribavirin.

Adamantane↗
PubMed2003

Clinical features and outcomes of paramyxoviral infection in lung transplant recipients treated with ribavirin.

BACKGROUND: Paramyxoviral infections are reported in 6% to 21% of lung transplant recipients. Aerosolized ribavirin is used to treat paramyoxviral infections, but data on outcomes of this treatment in lung transplant patients are limited. METHODS: Lung recipients treated with aerosolized ribavirin from 1992 through 2000 for pulmonary respiratory syncytial virus (RSV) or parainfluenza virus (PIV) infection were assessed for the following variables: age; gender; underlying diagnosis; time from transplantation; duration of illness; clinical symptoms; and change from baseline FEV(1) (forced expiratory volume in 1 second). Outcomes included FEV(1) values at 30 and 90 days, need for intubation, development of acute rejection or obliterative bronchiolitis (OB) in the year after treatment; and 90-day and overall mortality. RESULTS: Fifteen patients received ribavirin for a median of 5 days (range 3 to 7) for 17 episodes of RSV (n = 12) or PIV (n = 5) infection. The clinical presentations of RSV and PIV infection were similar. Infection occurred a median of 520 days (range 7 to 1700) after transplantation. Three episodes required intubation; 2 episodes were fatal accounting for a 90-day mortality per episode of 12%. The FEV(1) at presentation declined by 25% (range 4% to 44%) from baseline. In 3 patients the FEV(1) did not return to baseline by 90 days or thereafter. All 3 patients had underlying pulmonary fibrosis (IPF) vs no IPF in 0 of 9 evaluable patients who recovered (p = 0.009). There was no correlation between response to ribavirin and subsequent development of OB. CONCLUSIONS: About 33% of lung transplant patients with lower respiratory tract paramyxoviral infections who were treated with inhaled ribavirin died or did not return to baseline FEV(1). This effect was acute and not associated with later complications, including OB. Underlying IPF may be a risk factor for failure to return to baseline. Larger, prospective, multicenter studies are required to confirm these findings.

Administration, Inhalation↗
PubMed1992

Synthesis and antiviral properties of (+/-)-5'-noraristeromycin and related purine carbocyclic nucleosides. A new lead for anti-human cytomegalovirus agent design.

(+/-)-5'-Noraristeromycin (3) has been prepared in three steps beginning with the 2,3-O-isopropylidene derivative of (+/-)-(1 alpha, 2 beta, 3 beta, 4 alpha)-4-amino-1,2,3-cyclopentanetriol (7). Also prepared from the same starting material were the related hypoxanthine (4), guanine (5), and 2,6-diaminopurine (6) analogues. Compounds 3-6 were evaluated for antiviral activity against a large number of viruses with marked activity being observed for 3 towards vaccinia virus, human cytomegalovirus, vesicular stomatitis virus, parainfluenza (type 3) virus, measles virus, respiratory syncytial virus, reovirus (type 1), and the arenaviruses Junin and Tacaribe. None of the compounds showed cytotoxicity to the host cell monolayers used in the antiviral studies. Both 3 and 6 have been found to be inhibitors of S-adenosyl-L-homocysteine hydrolase (AdoHcy hydrolase), which likely accounts for their antiviral activity. Inhibition of AdoHcy hydrolase represents a new approach to human cytomegalovirus drug design that should be pursued. Also, the activity of 3 should be further scrutinized for the treatment of pox-, rhabdo-, paramyxo-, reo-, and arenavirus infections.

Adenosine↗
PubMed2004

Inhibition of respiratory viruses by nasally administered siRNA.

Respiratory syncytial virus (RSV) and parainfluenza virus (PIV) are two respiratory pathogens of paramount medical significance that exert high mortality. At present, there is no reliable vaccine or antiviral drug against either virus. Using an RNA interference (RNAi) approach, we show that individual as well as joint infection by RSV and PIV can be specifically prevented and inhibited by short interfering RNAs (siRNAs), instilled intranasally in the mouse, with or without transfection reagents. The degree of protection matched the antiviral activity of the siRNA in cell culture, allowing an avenue for quick screening of an efficacious siRNA. When targeting both viruses in a joint infection, excess of one siRNA moderated the inhibitory effect of the other, suggesting competition for the RNAi machinery. Our results suggest that, if properly designed, low dosages of inhaled siRNA might offer a fast, potent and easily administrable antiviral regimen against respiratory viral diseases in humans.

Animals↗
PubMed1992

In vitro virucidal effects of Allium sativum (garlic) extract and compounds.

Garlic (Allium sativum) has been shown to have antiviral activity, but the compounds responsible have not been identified. Using direct pre-infection incubation assays, we determined the in vitro virucidal effects of fresh garlic extract, its polar fraction, and the following garlic associated compounds: diallyl thiosulfinate (allicin), allyl methyl thiosulfinate, methyl allyl thiosulfinate, ajoene, alliin, deoxyalliin, diallyl disulfide, and diallyl trisulfide. Activity was determined against selected viruses including, herpes simplex virus type 1, herpes simplex virus type 2, parainfluenza virus type 3, vaccinia virus, vesicular stomatitis virus, and human rhinovirus type 2. The order for virucidal activity generally was: ajoene > allicin > allyl methyl thiosulfinate > methyl allyl thiosulfinate. Ajoene was found in oil-macerates of garlic but not in fresh garlic extracts. No activity was found for the garlic polar fraction, alliin, deoxyalliin, diallyl disulfide, or diallyl trisulfide. Fresh garlic extract, in which thiosulfinates appeared to be the active components, was virucidal to each virus tested. The predominant thiosulfinate in fresh garlic extract was allicin. Lack of reduction in yields of infectious virus indicated undetectable levels of intracellular antiviral activity for either allicin or fresh garlic extract. Furthermore, concentrations that were virucidal were also toxic to HeLa and Vero cells. Virucidal assay results were not influenced by cytotoxicity since the compounds were diluted below toxic levels prior to assaying for infectious virus. These results indicate that virucidal activity and cytotoxicity may have depended upon the viral envelope and cell membrane, respectively. However, activity against non-enveloped virus may have been due to inhibition of viral adsorption or penetration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter.

Most paramyxoviruses circumvent the IFN response by blocking IFN signaling and limiting the production of IFN by virus-infected cells. Here we report that the highly conserved cysteine-rich C-terminal domain of the V proteins of a wide variety of paramyxoviruses binds melanoma differentiation-associated gene 5 (mda-5) product. mda-5 is an IFN-inducible host cell DExD/H box helicase that contains a caspase recruitment domain at its N terminus. Overexpression of mda-5 stimulated the basal activity of the IFN-beta promoter in reporter gene assays and significantly enhanced the activation of the IFN-beta promoter by intracellular dsRNA. Both these activities were repressed by coexpression of the V proteins of simian virus 5, human parainfluenza virus 2, mumps virus, Sendai virus, and Hendra virus. Similar results to the reporter assays were obtained by measuring IFN production. Inhibition of mda-5 by RNA interference or by dominant interfering forms of mda-5 significantly inhibited the activation of the IFN-beta promoter by dsRNA. It thus appears that mda-5 plays a central role in an intracellular signal transduction pathway that can lead to the activation of the IFN-beta promoter, and that the V proteins of paramyxoviruses interact with mda-5 to block its activity.

Animals↗
PubMed1998

HIV type-1 infection of the cotton rat (Sigmodon fulviventer and S. hispidus).

Cotton rats (Sigmodon hispidus and S. fulviventer) are susceptible to many viruses that infect humans (e.g., poliovirus, respiratory syncytial virus, influenza virus, adenovirus, and parainfluenza virus) and have been influential in developing therapeutic clinical intervention strategies for many viral infections of man. This study set out to determine whether cotton rats are susceptible to infection with HIV type 1 (HIV-1). Results indicate that HIV-1 does infect the cotton rat and S. fulviventer is more susceptible than S. hispidus. The virus was passaged from animal to animal for a total of three serial passages; but HIV replicated poorly in vivo, was only detectable as proviral DNA, and never exceeded one provirus per 1.8 x 10(5) cotton rat peripheral blood mononuclear cells. Infection induced a distinct and characteristic anti-HIV antibody response that, in some animals, included neutralizing antibodies, recognized all of the major HIV-1 antigens and the antibodies lasted out to 52 wk post-infection. Neonate S. fulviventer were not more susceptible to infection than adults. In vitro culture studies produced indirect evidence of viral replication by detection of viral gag gene RNA in reverse transcriptase-PCR assays on viral culture supernatants. Collectively, these results indicate that HIV-1 can replicate in a nontransgenic rodent and that this system may have potential as an animal model for HIV-1 infection if viral replication rates can be improved in vivo.

Animals↗
PubMed1997

Phosphorylation of Sendai virus phosphoprotein by cellular protein kinase C zeta.

The phosphoproteins (P) of nonsegmented negative strand RNA viruses are viral RNA polymerase subunits involved in both transcription and replication during the virus life cycle. Phosphorylation of P proteins in several negative strand RNA viruses by specific cellular kinases was found to be required for P protein function. In the present study, using bacterially expressed unphosphorylated P protein of Sendai virus, a mouse parainfluenza virus, we have shown that the major cellular kinase that phosphorylates P protein in vitro is biochemically and immunologically indistinguishable from protein kinase C (PKC) zeta isoform. PKC zeta was packaged into the Sendai virion and remained associated with purified viral ribonucleoprotein, where it phosphorylated both the P and the nucleocapsid protein in vitro. When PKC zeta-specific inhibitory pseudosubstrate peptide was introduced into LLC-MK2 cells prior to Sendai virus infection, production of progeny virus was dramatically attenuated, and kinetic analysis revealed that primary transcription was repressed. These data indicate that phosphorylation of the Sendai virus P protein by PKC zeta plays a critical role in the virus life cycle.

Animals↗
PubMed2005

Symptomatic respiratory syncytial virus infection in previously healthy young adults living in a crowded military environment.

BACKGROUND: Respiratory syncytial virus (RSV) infection is a potentially important cause of acute respiratory illness in many populations, including military recruits receiving basic training. Understanding the full impact of RSV infection is challenging because of difficulties in diagnosis and the limitations of past epidemiologic studies. In this study, we set out to determine the prevalence and clinical characteristics of RSV infection and infection caused by other common viral agents in a population of previously healthy young adults, namely, military recruits receiving basic training. METHODS: In addition to standard viral culture techniques, we employed serologic testing and a recently described, novel, highly sensitive real-time PCR and a molecular beacon probe assay for the detection of RSV infection. RESULTS: Among 256 military trainees with respiratory symptoms, RSV infection was identified in 11% by means of serologic testing and real-time PCR. Viral culture identified adenovirus in 48% of symptomatic recruits, influenza viruses in 11%, parainfluenza virus 3 in 3%, and enterovirus in <1%. The majority of recruits with RSV infection experienced a nonproductive cough, sore throat, and nasal congestion, and almost half reported symptoms of wheeze or shortness of breath. Almost all (94%) of the recruits lost > or =1 day(s) from training because of illness. CONCLUSIONS: This study demonstrates the challenges of diagnosis and clinical significance of RSV infection in symptomatic young adults. RSV may account for 11% of clinically important respiratory illnesses in this population, which is as much as 25% of previously undiagnosed illness. These results have implications for treatment and prevention of RSV in young adults.

Adolescent↗
PubMedDate not supplied

Epidemiology of acute respiratory infections in children of developing countries.

Acute respiratory infections cause four and a half million deaths among children every year, the overwhelming majority occurring in developing countries. Pneumonia unassociated with measles causes 70% of these deaths; post-measles pneumonia, 15%; pertussis, 10%; and bronchiolitis and croup syndromes, 5%. Both bacterial and viral pathogens are responsible for these deaths. The most important bacterial agents are Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus. The data on bacterial etiology of pneumonia during the first 3 months of life are limited, and almost no information on the role of chlamydia and pertussis in this age period is available. The distribution of viral pathogens in developing countries can be summarized as follows: respiratory syncytial virus, 15%-20%; parainfluenza viruses, 7%-10%; and influenza A and B viruses and adenovirus, 2%-4%. Mixed viral and bacterial infections occur frequently. Risk factors that increase the incidence and severity of lower respiratory infection in developing countries include large family size, lateness in the birth order, crowding, low birth weight, malnutrition, vitamin A deficiency, lack of breast feeding, pollution, and young age. Effective interventions for prevention and medical case management are urgently needed to save the lives of many children predisposed to severe disease.

Acute Disease↗
PubMedDate not supplied

Viral vaccines for the prevention of childhood pneumonia in developing nations: priorities and prospects.

In concert with bacteria, respiratory viruses play a major role in the high rates of acute lower respiratory infection (ALRI) experienced in developing nations. Respiratory syncytial virus, parainfluenza and influenza viruses, and the adenoviruses are the predominant viral causes of ALRI in both developed and developing regions. In this review, the epidemiologic data from developing nations for these viral infections are summarized and the current status of viral vaccines for prevention of ALRI are described. Among the questions to be addressed before these vaccines are used in developing nations are (1) the age-specific rates of infection and disease, (2) the effect of high-dose early exposure to these viruses, and (3) the effect of malnutrition on the immunogenicity of the vaccines. Prospective family studies and other community-based approaches will be required in the acquisition of these data.

Adenovirus Infections, Human↗
PubMed1995

Respiratory virus infections during anticancer treatment in children.

To evaluate the occurrence and clinical significance of respiratory virus infections in children during anticancer treatment, we studied 75 consecutive episodes of febrile infection in 32 children during 17 months. Viral antigen detection for 7 respiratory viruses, viral culture for rhinoviruses and enzyme immunoassay serology were used. Evidence for respiratory virus infection was found in 28 (37%) cases. Rhinovirus was the most common virus detected in 13 (17%) episodes. The other etiologic agents were respiratory syncytial virus (6 episodes), parainfluenza virus type 3 (5 episodes), adenovirus (4 episodes), influenza A virus (3 episodes), and influenza B virus (1 episode). Respiratory virus infections were diagnosed as often in leukopenic as in non-leukopenic patients (37% vs. 38%). In 4 cases bacteremic infection was diagnosed. We found no difference in serum C-reactive protein values when episodes positive for respiratory viruses were compared with virus-negative episodes. Our observations show that respiratory virus infections are common in febrile children receiving anticancer treatment. Diagnostic tests for respiratory viruses should be used more often in evaluation of fever in these patients.

Adolescent↗
PubMed2004

Occurrence of respiratory virus: time, place and person.

BACKGROUND: Respiratory viruses account for most respiratory infections. Although analysis of epidemiologic information regarding viral seasonality, sites of transmission and susceptible populations is essential to devising strategies for limiting epidemics, few long term epidemiologic studies have addressed these questions. METHODS: Epidemiologic findings identifying susceptible populations, as well as temporal and geographic patterns of infection with influenza virus, respiratory syncytial virus, rhinovirus and parainfluenza virus were reviewed. CONCLUSIONS: Influenza is the virus most frequently associated with outbreaks of respiratory infection resulting in medical consultation as well as virus-related lethality. Similar symptom profiles and overlapping seasonality of respiratory syncytial virus and other viruses may sometimes complicate surveillance and treatment. Although vaccination and antiviral drugs are virus-specific, factors that promote transmission and thus strategies for limiting outbreaks are similar for various respiratory viruses.

Adolescent↗
PubMed1991

Identification of several different lineages of measles virus.

The sequences of a region of the nucleocapsid protein gene, between nucleotides 1231 and 1686, encoding the C-terminal 151 amino acid residues of the nucleocapsid protein have been determined for 16 strains of measles virus. Analysis of this region showed that it is highly divergent (up to 7.2% divergence in the nucleotide sequence and 10.6% divergence in the amino acid sequence between most distant strains) and that several lineages of measles virus can be found to co-circulate at a given time. Some of the lineages show geographical restriction. The results for measles virus are similar to those reported for other human paramyxoviruses such as mumps virus, parainfluenza type 3 virus and the avian Newcastle disease virus.

Adolescent↗
PubMed2005

Human metapneumovirus infections in Mexico: epidemiological and clinical characteristics.

The human metapneumovirus (hMPV) is a recently described respiratory RNA virus that mainly affects children. To date there has not been a report that describes the detection of this virus in Mexico. This study was performed to detect hMPV in hospitalized Mexican children with respiratory infections, and describe their epidemiological and clinical characteristics. Nasal wash samples from 558 children younger than 3 years of age with the admission diagnosis of a respiratory tract infection were evaluated. Respiratory viruses were detected in 221 children [respiratory syncytial virus (RSV), 193 (34.6 %); influenza virus, 13 (2.3 %); parainfluenza viruses, 15 (2.7 %)]. Respiratory secretions of 323 children in whom the presence of these viruses was excluded (131 admitted during the 2002-2003 respiratory season and 192 during the 2003-2004 season) were tested for hMPV infection. The hMPV genome was detected in 34 specimens by amplification using real-time RT-PCR. Sequencing of amplicons and phylogenetic analysis indicated the predominance of genotype A hMPV. The months with the highest number of hMPV detections were February and March. During the 2002-2003 season hMPV activity peaked after the RSV season. During the 2003-2004 season hMPV and RSV epidemics occurred simultaneously. The clinical presentation of an hMPV infection was indistinguishable from other respiratory infections. Except for one death, the outcomes of the hMPV infections were good. In this study, among the viruses routinely tested for, hMPV was the second most common agent, after RSV, in children younger than 3 years of age hospitalized with respiratory tract infections.

Child, Preschool↗
PubMed2004

Identification of small-animal and primate models for evaluation of vaccine candidates for human metapneumovirus (hMPV) and implications for hMPV vaccine design.

Human metapneumovirus (hMPV), a recently identified paramyxovirus, is the causative agent of respiratory tract disease in young children. Epidemiological studies have established the presence of hMPV in retrospective as well as current clinical samples in Europe, USA, Canada, Hong Kong and Australia. The hMPV disease incidence rate varied from 7 to 12 %. This rate of disease attack places hMPV in severity between respiratory syncytial virus and human parainfluenza virus type 3, two common respiratory pathogens of young children, the elderly and immunosuppressed individuals. To evaluate the effectiveness and safety of future hMPV antiviral drugs, therapeutic and prophylactic monoclonal antibodies (mAbs), and vaccine candidates, it was necessary to identify small-animal and primate models that efficiently supported hMPV replication in the respiratory tract and produced neutralizing serum antibodies, commonly a clinical correlate of protection in humans. In this study, various rodents (mice, cotton rats, hamsters and ferrets) and two primate species, rhesus macaques and African green monkeys (AGMs), were evaluated for hMPV replication in the respiratory tract. The results showed that hamsters, ferrets and AGMs supported hMPV replication efficiently and produced high levels of hMPV-neutralizing antibody titres. Hamsters vaccinated with subgroup A hMPV were protected from challenge with subgroup A or subgroup B hMPV, which has implications for hMPV vaccine design. Although these animal models do not mimic human hMPV disease signs, they will nevertheless be invaluable for the future evaluation of hMPV antivirals, mAbs and vaccines.

Animals↗
PubMed1985

Characterization of scrapie agent isolated from sheep in Japan.

A pathogenic agent isolated in mice from the brain of a sheep affected by scrapie-like disease was characterized. The incubation period of the disease in the primary transmission from the sheep to mice was longer than in the secondary and the tertiary transmission in the same strain of mice. Progressive dilution of the inoculum caused prolongation of the incubation period. The infectivity of the agent in a 10% brain homogenate persisted, but decreased about 10(3) to 10(4) times after heating at 100 C for 30 min. Histological changes in the diseased mouse brains consisted of vacuolation of the nerve cells and spongiform degeneration in the gray matter of the central nervous system. Fine rod-shaped granulae with a length of 3 to 5 nm were observed within the swollen neuropil, axon, and perivascular astrocytic process. No serum antibodies against available mouse viruses, parainfluenza type 1 virus, lymphocytic choriomeningitis virus, and mouse reovirus type 3, were detected in any mice used in the experiments. These findings demonstrate that the disease of the sheep was the first case of scrapie in Japan.

Animals↗
PubMed2001

Paramyxovirus accessory proteins as interferon antagonists.

A new role of the Paramyxovirus accessory proteins has been uncovered. The P gene of the subfamily Paramyxovirinae encodes accessory proteins including the V and/or C protein by means of pseudotemplated nucleotide addition (RNA editing) or by overlapping open reading frame. The Respirovirus (Sendai virus and human parainfluenza virus (hPIV)3) and Rubulavirus (simian virus (SV)5, SV41, mumps virus and hPIV2) circumvent the interferon (IFN) response by inhibiting IFN signaling. The responsible genes were mapped to the C gene for SeV and the V gene for rubulaviruses. On the other hand, wild type measles viruses isolated from clinical specimens suppress production of IFN, although responsible viral factors remain to be identified. Both human and bovine respiratory syncytial viruses (RSVs) counteract the antiviral effect of IFN with inhibiting neither IFN signaling nor IFN production. Bovine RSV NS1 and NS2 proteins cooperatively antagonize the antiviral effect of IFN. Studies on the molecular mechanism by which viruses circumvent the host IFN response will not only illustrate co-evolution of virus strategies of immune evasion but also provide basic information useful for engineering novel antiviral drugs as well as recombinant live vaccine.

Base Sequence↗