Use of Cotton Rats to Evaluate the Efficacy of Antivirals in Treatment of Measles Virus Infections

ABSTRACT No practical animal models for the testing of chemotherapeutic or biologic agents identified in cell culture assays as being active against measles virus (MV) are currently available. Cotton rats may serve this purpose. To evaluate this possibility, 5-ethynyl-1-β-d-ribofuranosylimidazole-4-carboxamide (EICAR) and poly(acrylamidomethyl propanesulfonate) (PAMPS), two compounds that have been reported to inhibit MV in vitro, and ribavirin, an established antiviral drug with MV-inhibitory activity, were evaluated for their antiviral activities against MV and respiratory syncytial virus (RSV) in tissue culture and in hispid cotton rats. A single administration of PAMPS markedly inhibited pulmonary RSV or MV replication (>3 log10 reduction in pulmonary titer compared to that for controls), but only if this compound was administered intranasally at about the time of virus inoculation. Both EICAR and ribavirin exhibited therapeutic activity against RSV and MV in cotton rats when they were administered parenterally. However, both of these compounds were less effective against MV. On the basis of the pulmonary virus titers on day 4 after virus inoculation, the minimal efficacious dose of EICAR against MV (120 mg/kg of body weight/day when delivered intraperitoneally twice daily) appeared to be three times lower against this virus than that of ribavirin delivered at a similar dose (i.e., 360 mg/kg/day). These findings correlated with those obtained in vitro. The data obtained suggest that cotton rats may indeed be useful for the initial evaluation of the activities of antiviral agents against MV.

Download Full-text

Antiviral Activity of Favipiravir (T-705) against a Broad Range of ParamyxovirusesIn Vitroand against Human Metapneumovirus in Hamsters

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00709-16 ◽

2016 ◽

Vol 60 (8) ◽

pp. 4620-4629 ◽

Cited By ~ 20

Author(s):

D. Jochmans ◽

S. van Nieuwkoop ◽

S. L. Smits ◽

J. Neyts ◽

R. A. M. Fouchier ◽

...

Keyword(s):

Antiviral Activity ◽

Measles Virus ◽

Rna Virus ◽

Antiviral Drug ◽

Specific Effect ◽

Human Metapneumovirus ◽

Drug Candidate ◽

Emerging Viruses ◽

Syncytial Virus

ABSTRACTThe clinical impact of infections with respiratory viruses belonging to the familyParamyxoviridaeargues for the development of antiviral therapies with broad-spectrum activity. Favipiravir (T-705) has demonstrated potent antiviral activity against multiple RNA virus families and is presently in clinical evaluation for the treatment of influenza. Here we demonstratein vitroactivity of T-705 against the paramyxoviruses human metapneumovirus (HMPV), respiratory syncytial virus, human parainfluenza virus, measles virus, Newcastle disease virus, and avian metapneumovirus. In addition, we demonstrate activity against HMPV in hamsters. T-705 treatment inhibited replication of all paramyxoviruses testedin vitro, with 90% effective concentration (EC90) values of 8 to 40 μM. Treatment of HMPV-challenged hamsters with T-705 at 200 mg/kg of body weight/day resulted in 100% protection from infection of the lungs. In all treated and challenged animals, viral RNA remained detectable in the respiratory tract. The observation that T-705 treatment had a significant effect on infectious viral titers, with a limited effect on viral genome titers, is in agreement with its proposed mode of action of viral mutagenesis. However, next-generation sequencing of viral genomes isolated from treated and challenged hamsters did not reveal (hyper)mutation. Polymerase activity assays revealed a specific effect of T-705 on the activity of the HMPV polymerase. With the reported antiviral activity of T-705 against a broad range of RNA virus families, this small molecule is a promising broad-range antiviral drug candidate for limiting the viral burden of paramyxoviruses and for evaluation for treatment of infections with (re)emerging viruses, such as the henipaviruses.

Download Full-text

Antiviral Activities of Diarylheptanoids Isolated from Alpinia officinarum against Respiratory Syncytial Virus, Poliovirus, Measles Virus, and Herpes Simplex Virus Type 1 in vitro

Natural Product Communications ◽

10.1177/1934578x1100601222 ◽

2011 ◽

Vol 6 (12) ◽

pp. 1934578X1100601 ◽

Cited By ~ 5

Author(s):

Katsuhiko Konno ◽

Rie Sawamura ◽

Yi Sun ◽

Ken Yasukawa ◽

Tomomi Shimizu ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Herpes Simplex ◽

Measles Virus ◽

Alpinia Officinarum ◽

Antiviral Activities ◽

Syncytial Virus ◽

Simplex Virus ◽

Hsv 1

Alpinia officinarum has been used as a folk medicine and contains diarylheptanoids that have various biological activities. However, their antiviral activities are less elucidated. We examined the antiviral activities of nine diarylheptanoids isolated from A. officinarum against respiratory syncytial virus (RSV), poliovirus, measles virus, and herpes simplex virus type 1 (HSV-1) using a plaque reduction assay. The 50% inhibitory concentrations of seven of the nine diarylheptanoids for RSV were moderately but significantly lower than their 50% cytotoxic concentrations, as determined by a trypan blue exclusion assay. Four diarylheptanoids with anti-RSV activity also showed anti-poliovirus and anti-measles virus activities and three of the four exhibited anti-HSV-1 activity. Thus, seven of the nine diarylheptanoids examined exhibited potential antiviral activity against RSV, and most of the diarylheptanoids with anti-RSV activity, including two diarylheptanoids without anti-RSV activity, were effective against poliovirus, measles virus, and/or HSV-1 in vitro. Diarylheptanoids were suggested to have a broad spectrum of antiviral activity.

Download Full-text

Antiviral Activities of Mizoribine and other Inosine Monophosphate Dehydrogenase Inhibitors against Several Ortho- and Paramyxoviruses

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029400500603 ◽

1994 ◽

Vol 5 (6) ◽

pp. 366-371 ◽

Cited By ~ 19

Author(s):

Y. Kosugi ◽

Y. Saito ◽

S. Mori ◽

J. Watanabe ◽

M. Baba ◽

...

Keyword(s):

Mycophenolic Acid ◽

Measles Virus ◽

Influenza Viruses ◽

Guanosine Monophosphate ◽

Host Cells ◽

Inosine Monophosphate Dehydrogenase ◽

Inosine Monophosphate ◽

Antiviral Activities ◽

Syncytial Virus

Mizoribine (4-carbamoyl-1-β-D-ribofuranosylimidazo-lelium-5-olate), EICAR (5-ethynyl-1-β-D-ribofuranosylimi-dazole-4-carboxamide), mycophenolic acid and ribavirin are antiviral agents targeted for inosine monophosphate (IMP) dehydrogenase. These compounds have been examined for their activities against orthomyxoviruses [influenza viruses (FluV)] and paramyxoviruses [parainfluenza viruses (PFIuV), mumps virus, measles virus (MLSV) and respiratory syncytial virus (RSV)] in vitro. Mizoribine was 1- to 9-fold more active than ribavirin against RSV, PFIuV and MLSV. EICAR and mycophenolic acid showed higher potency than mizoribine and ribavirin against all myxoviruses examined. None of the four compounds examined proved cytotoxic to stationary host cells (HeLa, Vero and MDCK) at a concentration of 200 μg ml−1 or more. On the other hand, EICAR and mycophenolic acid were toxic to rapidly growing cells at concentrations of 2.2-9 and 0.1-1.1 μg ml−1, respectively. Mizoribine and ribavirin showed cytotoxicity to the growing cells at higher concentrations (12-51 μg ml−1). The antiviral activities of mizoribine against FluV and RSV were reversed by 25-100 μm of each of guanosine and guanosine monophosphate (GMP). The antiviral activity of ribavirin against FluV was reversed by 25 μg of each of guanosine and GMP, while its activity against RSV was reversed by ≥ 100 μm of each of these compounds. Neither xanthosine nor xanthosine monophosphate (XMP) reversed the antiviral effects of mizoribine and ribavirin at concentrations of 300 μM. Concentrations 9 times higher than the median effective doses (EC50) of mizoribine and ribavirin inhibited the growth of RSV in HeLa cells as determined in an assay of infectious virus yield. Mizoribin should be further pursued as a candidate drug for the treatment of ortho- and paramyxovirus infections.

Download Full-text

Biological Response Modifiers in Combination with Antivirals against Experimentally-Induced Virus Infections

Canadian Journal of Infectious Diseases ◽

10.1155/1992/506386 ◽

1992 ◽

Vol 3 (suppl b) ◽

pp. 49-54 ◽

Cited By ~ 1

Author(s):

Robert W Sidwell ◽

John H Huffman ◽

Donald F Smee ◽

John Gilbert ◽

Roland K Robins ◽

...

Keyword(s):

Antiviral Agents ◽

Antiviral Drug ◽

Biological Response ◽

Therapeutic Index ◽

Biological Response Modifiers ◽

Virus Infections ◽

Virus Inoculation ◽

Virus Recovery ◽

Punta Toro Virus ◽

Experimentally Induced

Biological response modifiers (BRMs) have particular promise when used in combination with more standard antiviral agents for treatment of viral diseases. Reported here are a series of studies which have used two BRMs in combination with the antiviral drug, ribavirin (l-β-o-ribofuranosyl-1,2,4-triazole-3-carboxamide) in treatment of experimentally-induced phlebovirus (Punta Toro virus) infections in mice. The positive BRMs studied include bropirimine (2-amino-5-bromo-6-phenyl-4[3H]pyrimidinone) given orally at dosages of 25, 50 and 100 mg/kg/day beginning 24 h after virus inoculation. and 7-thia-8-oxoguanosine administered intrapcritoneally at dosages of 6.3, 12.5 and 25 mg/kg/day given 24 and 31 h after virus inoculation. In each experiment. multiple dosages of both BRM and ribavirin were selected to range from ineffective levels to, in certain cases with ribavirin, lethally toxic levels. Ribavirin was always administered orally twice daily for three days starting 24 h after virus inoculation. Both drug combinations were considered synergistic, increasing the therapeutic index compared to either drug used alone, and significantly reducing the evidence of ribavirin toxicity. Efficacy was seen as increased survivors, decreased virus recovery from tissues and blood. and lowered glutamic oxalic and pyruvic transaminase levels in the serum.

Download Full-text

Amantadine Inhibits SARS-CoV-2 In Vitro

Viruses ◽

10.3390/v13040539 ◽

2021 ◽

Vol 13 (4) ◽

pp. 539

Author(s):

Klaus Fink ◽

Andreas Nitsche ◽

Markus Neumann ◽

Marica Grossegesse ◽

Karl-Heinz Eisele ◽

...

Keyword(s):

Influenza A ◽

Antiviral Agents ◽

Antiviral Drug ◽

Systemic Exposure ◽

Topical Administration ◽

Counter Measures ◽

Travel Restrictions ◽

Drug Treatments ◽

Intranasal Instillation

Since the SARS-CoV-2 pandemic started in late 2019, the search for protective vaccines and for drug treatments has become mandatory to fight the global health emergency. Travel restrictions, social distancing, and face masks are suitable counter measures, but may not bring the pandemic under control because people will inadvertently or at a certain degree of restriction severity or duration become incompliant with the regulations. Even if vaccines are approved, the need for antiviral agents against SARS-CoV-2 will persist. However, unequivocal evidence for efficacy against SARS-CoV-2 has not been demonstrated for any of the repurposed antiviral drugs so far. Amantadine was approved as an antiviral drug against influenza A, and antiviral activity against SARS-CoV-2 has been reasoned by analogy but without data. We tested the efficacy of amantadine in vitro in Vero E6 cells infected with SARS-CoV-2. Indeed, amantadine inhibited SARS-CoV-2 replication in two separate experiments with IC50 concentrations between 83 and 119 µM. Although these IC50 concentrations are above therapeutic amantadine levels after systemic administration, topical administration by inhalation or intranasal instillation may result in sufficient amantadine concentration in the airway epithelium without high systemic exposure. However, further studies in other models are needed to prove this hypothesis.

Download Full-text

In Vitro and In Vivo Fitness of Respiratory Syncytial Virus Monoclonal Antibody Escape Mutants

Journal of Virology ◽

10.1128/jvi.01387-06 ◽

2006 ◽

Vol 80 (23) ◽

pp. 11651-11657 ◽

Cited By ~ 20

Author(s):

Xiaodong Zhao ◽

Enmei Liu ◽

Fu-Ping Chen ◽

Wayne M. Sullender

Keyword(s):

Cell Culture ◽

Monoclonal Antibody ◽

Respiratory Syncytial Virus ◽

Viral Population ◽

Nucleotide Substitutions ◽

Cotton Rats ◽

Syncytial Virus ◽

In Vivo Growth

ABSTRACT Respiratory syncytial virus (RSV) is the only infectious disease for which a monoclonal antibody (MAb) is used in humans. Palivizumab (PZ) is a humanized murine MAb to the F protein of RSV. PZ-resistant viruses appear after in vitro and in vivo growth of RSV in the presence of PZ. Fitness for replication could be a determinant of the likelihood of dissemination of resistant viruses. We assessed the fitness of two PZ-resistant viruses (F212 and MP4). F212 grew less well in cell culture than the parent A2 virus and was predicted to be less fit than A2. Equal amounts of F212 and A2 were mixed and passaged in cell culture. F212 disappeared from the viral population, indicating it was less fit than the A2 virus. The MP4 virus grew as well as A2 in culture and in cotton rats. A2/MP4 virus input ratios of 1:1, 10:1, 100:1, and 1,000:1 were compared in competitive replication. For all input ratios except 1,000:1, the MP4 virus became dominant, supplanting the A2 virus. The MP4 virus also dominated the A2 virus during growth in cotton rats. Thus, the mutant MP4 virus was more fit than A2 virus in both in vitro and in vivo competitive replication. Whether this fitness difference was due to the identified nucleotide substitutions in the F gene or to mutations elsewhere in the genome is unknown. Understanding the mechanisms by which mutant virus fitness increased or decreased could prove useful for consideration in attenuated vaccine design efforts.

Download Full-text

Recombinant Green Fluorescent Protein-Expressing Human Cytomegalovirus as a Tool for Screening Antiviral Agents

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.6.1588-1597.2000 ◽

2000 ◽

Vol 44 (6) ◽

pp. 1588-1597 ◽

Cited By ~ 101

Author(s):

Manfred Marschall ◽

Martina Freitag ◽

Sigrid Weiler ◽

Gabriele Sorg ◽

Thomas Stamminger

Keyword(s):

Green Fluorescent Protein ◽

Human Cytomegalovirus ◽

Fluorescent Protein ◽

Antiviral Agents ◽

Inhibitory Effects ◽

Plaque Reduction Assay ◽

Human Fibroblast Cultures ◽

Antiviral Activities ◽

Green Fluorescent

ABSTRACT A recombinant human cytomegalovirus (AD169-GFP) expressing green fluorescent protein was generated by homologous recombination. Infection of human fibroblast cultures with AD169-GFP virus produced stable and readily detectable amounts of GFP signals which were quantitated by automated fluorometry. Hereby, high levels of sensitivity and reproducibility could be achieved, compared to those with the conventional plaque reduction assay. Antiviral activities were determined for four reference compounds as well as a set of putative novel cytomegalovirus inhibitors. The results obtained were exactly in line with the known characteristics of reference compounds and furthermore revealed distinct antiviral activities of novel in vitro inhibitors. The fluorometric data could be confirmed by GFP-based flow cytometry and fluorescence microscopy. In addition, laboratory virus variants derived from the recombinant AD169-GFP virus provided further possibilities for study of the characteristics of drug resistance. The GFP-based antiviral assay appeared to be very reliable for measuring virus-inhibitory effects in concentration- and time-dependent fashions and might also be adaptable for high-throughput screenings of cytomegalovirus-specific antiviral agents.

Download Full-text

Inhibition of B Virus (Macacine herpesvirus 1) by Conventional and Experimental Antiviral Compounds

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01435-08 ◽

2009 ◽

Vol 54 (1) ◽

pp. 452-459 ◽

Cited By ~ 6

Author(s):

P. W. Krug ◽

R. F. Schinazi ◽

J. K. Hilliard

Keyword(s):

Antiviral Treatment ◽

Antiviral Agents ◽

Antiviral Drug ◽

Nucleoside Analogs ◽

High Morbidity ◽

Virus Infections ◽

Experimental Drugs ◽

B Virus ◽

Simplex Virus ◽

Virus Isolates

ABSTRACT B virus infection of humans results in high morbidity and mortality in as many as 80% of identified cases. The main objective of this study was to conduct a comparative analysis of conventional and experimental antiviral drug susceptibilities of B virus isolates from multiple macaque species and zoonotically infected humans. We used a plaque reduction assay to establish the effective inhibitory doses of acyclovir, ganciclovir, and vidarabine, as well as those of a group of experimental nucleoside analogs with known anti-herpes simplex virus activity. Four of the experimental drugs tested were 10- to 100-fold more potent inhibitors of B virus replication than conventional antiviral agents. Drug efficacies were similar for multiple B virus isolates tested, with variations within 2-fold of the median effective concentration (EC50) for each drug, and each EC50 was considerably lower than those for B virus thymidine kinase (TK) mutants. We observed no differences in the viral TK amino acid sequence between B virus isolates from rhesus monkeys and those from human zoonoses. Differences in the TK protein sequence between cynomolgus and pigtail macaque B virus isolates did not affect drug sensitivity except in the case of one compound. Taken together, these data suggest that future B virus zoonoses will respond consistently to conventional antiviral treatment. Further, the considerably higher potency of FEAU (2′-fluoro-5-ethyl-Ara-U) than of conventional antiviral drugs argues for its compassionate use in advanced human B virus infections.

Download Full-text

Mitoxantrone Shows In Vitro, but Not In Vivo Antiviral Activity against Human Respiratory Syncytial Virus

Biomedicines ◽

10.3390/biomedicines9091176 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1176

Author(s):

Patricia G. de la Sota ◽

Elena Lorente ◽

Laura Notario ◽

Carmen Mir ◽

Oscar Zaragoza ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Respiratory Infections ◽

The Elderly ◽

Human Respiratory Syncytial Virus ◽

Mice Model ◽

Drug Candidates ◽

Antiviral Activities ◽

Syncytial Virus

Human respiratory syncytial virus (HRSV) is the most common cause of severe respiratory infections in infants and young children, often leading to hospitalization. In addition, this virus poses a serious health risk in immunocompromised individuals and the elderly. HRSV is also a major nosocomial hazard in healthcare service units for patients of all ages. Therefore, the development of antiviral treatments against HRSV is a global health priority. In this study, mitoxantrone, a synthetic anthraquinone with previously reported in vitro antiprotozoal and antiviral activities, inhibits HRSV replication in vitro, but not in vivo in a mice model. These results have implications for preclinical studies of some drug candidates.

Download Full-text

Potential Benefits of Antiviral African Medicinal Plants in the Management of Viral Infections: Systematic Review

Frontiers in Pharmacology ◽

10.3389/fphar.2021.682794 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tamirat Bekele Beressa ◽

Serawit Deyno ◽

Andrew G. Mtewa ◽

Namuli Aidah ◽

Naasson Tuyiringire ◽

...

Keyword(s):

Medicinal Plants ◽

Measles Virus ◽

Viral Infections ◽

Yellow Fever Virus ◽

Rift Valley Fever Virus ◽

Evidence Synthesis ◽

Fever Virus ◽

Antiviral Activities

Background: Viruses cause various human diseases, some of which become pandemic outbreaks. This study synthesized evidence on antiviral medicinal plants in Africa which could potentially be further studied for viral infections including Coronavirus disease 2019 (COVID-19) treatment.Methods: PUBMED, CINAHIL, Scopus, Google Scholar, and Google databases were searched through keywords; antiviral, plant, herb, and Africa were combined using “AND” and “OR”. In-vitro studies, in-vivo studies, or clinical trials on botanical medicine used for the treatment of viruses in Africa were included.Results: Thirty-six studies were included in the evidence synthesis. Three hundred and twenty-eight plants were screened for antiviral activities of which 127 showed noteworthy activities against 25 viral species. These, were Poliovirus (42 plants), HSV (34 plants), Coxsackievirus (16 plants), Rhinovirus (14plants), Influenza (12 plants), Astrovirus (11 plants), SARS-CoV-2 (10 plants), HIV (10 plants), Echovirus (8 plants), Parvovirus (6 plants), Semiliki forest virus (5 plants), Measles virus (5 plants), Hepatitis virus (3 plants), Canine distemper virus (3 plants), Zika virus (2 plants), Vesicular stomatitis virus T2 (2 plants). Feline herpesvirus (FHV-1), Enterovirus, Dengue virus, Ebola virus, Chikungunya virus, Yellow fever virus, Respiratory syncytial virus, Rift Valley fever virus, Human cytomegalovirus each showed sensitivities to one plant.Conclusion: The current study provided a list of African medicinal plants which demonstrated antiviral activities and could potentially be candidates for COVID-19 treatment. However, all studies were preliminary and in vitro screening. Further in vivo studies are required for plant-based management of viral diseases.

Download Full-text