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Clinical Infectious Diseases : An... Feb 1996The early preclinical development of an antiviral agent is accomplished essentially in two stages. The first stage consists of gathering data to estimate the potential... (Review)
Review
The early preclinical development of an antiviral agent is accomplished essentially in two stages. The first stage consists of gathering data to estimate the potential therapeutic index of the agent. This process includes testing for antiviral activity and for cytotoxicity in vitro and performing preliminary pharmacokinetic and toxicology studies in vivo. The second stage consists of carrying out more-extensive safety (toxicology) studies to determine any significant potential toxicities before the agent is used in humans. Chronic-toxicity studies, reproductive toxicity studies, and carcinogenesis bioassays are performed to support clinical trials of longer duration and, ultimately, approval of efficacious antiviral agents. It is essential to identify toxicities early in the developmental process for both safety and economic reasons. Progress in determining the mechanisms of specific toxicities will greatly aid in risk assessment and in our ability to predict and avoid these toxicities.
Topics: Animals; Antiviral Agents; Clinical Trials as Topic; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Toxicity Tests
PubMed: 8838196
DOI: 10.1093/clinids/22.2.355 -
Virology Journal Apr 2021Sacbrood is an infectious disease of the honey bee caused by Scbrood virus (SBV) which belongs to the family Iflaviridae and is especially lethal for Asian honeybee Apis...
BACKGROUND
Sacbrood is an infectious disease of the honey bee caused by Scbrood virus (SBV) which belongs to the family Iflaviridae and is especially lethal for Asian honeybee Apis cerana. Chinese Sacbrood virus (CSBV) is a geographic strain of SBV. Currently, there is a lack of an effective antiviral agent for controlling CSBV infection in honey bees.
METHODS
Here, we explored the antiviral effect of a Chinese medicinal herb Radix isatidis on CSBV infection in A. cerana by inoculating the 3rd instar larvae with purified CSBV and treating the infected bee larvae with R. isatidis extract at the same time. The growth, development, and survival of larvae between the control and treatment groups were compared. The CSBV copy number at the 4th instar, 5th instar, and 6th instar larvae was measured by the absolute quantification PCR method.
RESULTS
Bioassays revealed that R. isatidis extract significantly inhibited the replication of CSBV, mitigated the impacts of CSBV on larval growth and development, reduced the mortality of CSBV-infected A. cerana larvae, and modulated the expression of immune transcripts in infected bees.
CONCLUSION
Although the mechanism underlying the inhibition of CSBV replication by the medicine plant will require further investigation, this study demonstrated the antiviral activity of R. isatidis extract and provides a potential strategy for controlling SBV infection in honey bees.
Topics: Animals; Antiviral Agents; Bees; Larva; Plant Extracts; Plants, Medicinal; RNA Viruses
PubMed: 33882983
DOI: 10.1186/s12985-021-01550-y -
Journal of Agricultural and Food... Mar 2020Previously, we reported for the first time that harmala alkaloids harmine and tetrahydroharmine exhibit activity against plant viruses, and we developed an analogue,...
Previously, we reported for the first time that harmala alkaloids harmine and tetrahydroharmine exhibit activity against plant viruses, and we developed an analogue, designated NK0209, that efficiently prevents and controls plant virus diseases. Here, to investigate the influence of the spatial configuration of NK0209 on its antiviral activities, we synthesized its four optical isomers, determined their configurations, and evaluated their activities against tobacco mosaic virus. All four isomers were significantly more active than ningnanmycin, which is one of the most successful commercial antiviral agents, with in vivo inactivation, cure, and protection rates of 57.3 ± 1.9, 54.2 ± 3.3, and 55.0 ± 4.1% at 500 μg/mL. Furthermore, analysis of structure-activity relationships demonstrated for the first time that the spatial conformation of NK0209 is an important determinant of its antiviral activity, and our results provide information about the possible optimum configuration for interaction of this molecule with its target protein.
Topics: Antiviral Agents; Drug Design; Harmine; Isomerism; Molecular Conformation; Plant Diseases; Plant Viruses; Structure-Activity Relationship; Tobacco Mosaic Virus
PubMed: 32023057
DOI: 10.1021/acs.jafc.9b07694 -
Virologica Sinica Apr 2023Porcine epidemic diarrhea virus (PEDV), an enteropathogenic coronavirus, has catastrophic impacts on the global pig industry. However, there remain no effective drugs...
Porcine epidemic diarrhea virus (PEDV), an enteropathogenic coronavirus, has catastrophic impacts on the global pig industry. However, there remain no effective drugs against PEDV infection. In this study, we utilized a recombinant PEDV expressing renilla luciferase (PEDV-Rluc) to screen potential anti-PEDV agents from an FDA-approved drug library in Vero cells. Four compounds were identified that significantly decreased luciferase activity of PEDV-Rluc. Among them, niclosamide was further characterized because it exhibited the most potent antiviral activity with the highest selectivity index. It can efficiently inhibit viral RNA synthesis, protein expression and viral progeny production of classical and variant PEDV strains in a dose-dependent manner. Time of addition assay showed that niclosamide exhibited potent anti-PEDV activity when added simultaneously with or after virus infection. Furthermore, niclosamide significantly inhibited the entry stage of PEDV infection by affecting viral internalization rather than viral attachment to cells. In addition, a combination with other small molecule inhibitors of endosomal acidification enhanced the anti-PEDV effect of niclosamide in vitro. Taken together, these findings suggested that niclosamide is a novel antiviral agent that might provide a basis for the development of novel drug therapies against PEDV and other related pathogenic coronavirus infections.
Topics: Chlorocebus aethiops; Animals; Swine; Antiviral Agents; Vero Cells; Porcine epidemic diarrhea virus; Niclosamide; Virus Internalization; Coronavirus Infections; Swine Diseases
PubMed: 36702255
DOI: 10.1016/j.virs.2023.01.008 -
ACS Chemical Biology Feb 2015Inhibitors of the PI3-kinase/Akt (protein kinase B) pathway are under investigation as anticancer and antiviral agents. Akt inhibitor-IV (ChemBridge 5233705, CAS...
Inhibitors of the PI3-kinase/Akt (protein kinase B) pathway are under investigation as anticancer and antiviral agents. Akt inhibitor-IV (ChemBridge 5233705, CAS 681281-88-9, AKTIV), a small molecule reported to inhibit this pathway, exhibits potent anticancer and broad-spectrum antiviral activity. However, depending on concentration, this cationic benzimidazole derivative exhibits paradoxical positive or negative effects on the phosphorylation of Akt that are not well understood. To elucidate its mechanism of action, we investigated its spectroscopic properties. This compound proved to be sufficiently fluorescent (excitation λmax = 388 nm, emission λmax = 460 nm) to enable examination of its uptake and distribution in living mammalian cells. Despite a low quantum yield of 0.0016, imaging of HeLa cells treated with AKTIV (1 μM, 5 min) by confocal laser scanning microscopy, with excitation at 405 nm, revealed extensive accumulation in mitochondria. Treatment of Jurkat lymphocytes with 1 μM AKTIV for 15 min caused accumulation to over 250 μM in these organelles, whereas treatment with 5 μM AKTIV yielded concentrations of over 1 mM in mitochondria, as analyzed by flow cytometry. This massive loading resulted in swelling of these organelles, followed by their apparent disintegration. These effects were associated with profound disruption of cellular bioenergetics including mitochondrial depolarization, diminished mitochondrial respiration, and release of reactive oxygen species. Because mitochondria play key roles in both cancer proliferation and viral replication, we conclude that the anticancer and antiviral activities of AKTIV predominantly result from its direct and immediate effects on the structure and function of mitochondria.
Topics: Antineoplastic Agents; Antiviral Agents; Benzimidazoles; Benzothiazoles; Flow Cytometry; HeLa Cells; Humans; Jurkat Cells; Membrane Potential, Mitochondrial; Microscopy, Confocal; Mitochondria; Molecular Structure; Reactive Oxygen Species
PubMed: 25415586
DOI: 10.1021/cb500856c -
Journal of Applied Microbiology May 2018With the emergence of antibiotic resistance, the interest for antimicrobial agents has recently increased again in public health. Copper was recognized in 2008 by the... (Review)
Review
With the emergence of antibiotic resistance, the interest for antimicrobial agents has recently increased again in public health. Copper was recognized in 2008 by the United States Environmental Protection Agency (EPA) as the first metallic antimicrobial agent. This led to many investigations of the various properties of copper as an antibacterial, antifungal and antiviral agent. This review summarizes the latest findings about 'contact killing', the mechanism of action of copper nanoparticles and the different ways micro-organisms develop resistance to copper.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Antiviral Agents; Copper; Drug Resistance, Microbial
PubMed: 29280540
DOI: 10.1111/jam.13681 -
Infectious Disorders Drug Targets 2024Monkeypox is a viral disease; its outbreak was recently declared a global emergency by the World Health Organization. For the first time, a monkeypox virus... (Review)
Review
Monkeypox is a viral disease; its outbreak was recently declared a global emergency by the World Health Organization. For the first time, a monkeypox virus (MPXV)-infected patient was found in India. Various researchers back-to-back tried to find the solution to this health emergency just after COVID-19. In this review, we discuss the current outbreak status of India, its transmission, virulence factors, symptoms, treatment, and the preventive guidelines generated by the Indian Health Ministry. We found that monkeypox virus (MPXV) disease is different from smallpox, and the age group between 30-40 years old is more prone to MPXV disease. We also found that, besides homosexuals, gays, bisexuals, and non-vegetarians, it also affects normal straight men and women who have no history of travel. Close contact should be avoided from rats, monkeys and sick people who are affected by monkeypox. To date, there are no monkeypox drugs, but Tecovirimat is more effective than other drugs that are used for other viral diseases like smallpox. Therefore, we need to develop an effective antiviral agent against the virulence factor of MXPV.
Topics: Animals; Female; Humans; Male; Antiviral Agents; Benzamides; Disease Outbreaks; India; Isoindoles; Monkeypox virus; Mpox (monkeypox); Phthalimides; Virulence Factors; Adult
PubMed: 38243966
DOI: 10.2174/0118715265258451231214063506 -
Molecules (Basel, Switzerland) Dec 2020Curcumin is a natural compound that has many medical applications. However, its low solubility and poor stability could impede its clinical applications. The present...
Development of Provesicular Nanodelivery System of Curcumin as a Safe and Effective Antiviral Agent: Statistical Optimization, In Vitro Characterization, and Antiviral Effectiveness.
Curcumin is a natural compound that has many medical applications. However, its low solubility and poor stability could impede its clinical applications. The present study aimed to formulate dry proniosomes to overcome these pitfalls and improve the therapeutic efficacy of Curcumin. Curcumin-loaded proniosomes were fabricated by the slurry method according to 3 factorial design using Design-Expert software to demonstrate the impact of different independent variables on entrapment efficiency (EE%) and % drug released after 12 h (Q). The optimized formula (F5) was selected according to the desirability criteria. F5 exhibited good flowability and appeared, after reconstitution, as spherical nanovesicles with EE% of 89.94 ± 2.31% and Q of 70.89 ± 1.62%. F5 demonstrated higher stability and a significant enhancement of Q than the corresponding niosomes. The docking study investigated the ability of Curcumin to bind effectively with the active site of DNA polymerase of Herpes simplex virus (HSV). The antiviral activity and the safety of F5 were significantly higher than Curcumin. F5 improved the safety of Acyclovir (ACV) and reduced its effective dose that produced a 100% reduction of viral plaques. Proniosomes could be promising stable carriers of Curcumin to be used as a safe and efficient antiviral agent.
Topics: Animals; Antineoplastic Agents; Antiviral Agents; Chlorocebus aethiops; Curcumin; Drug Delivery Systems; Herpes Simplex; In Vitro Techniques; Liposomes; Nanoparticles; Simplexvirus; Vero Cells
PubMed: 33271831
DOI: 10.3390/molecules25235668 -
American Journal of Health-system... Oct 2006The implications of the findings from clinical studies and pharmacokinetic analyses of the antiviral agent valganciclovir for dosing of the drug to prevent... (Review)
Review
PURPOSE
The implications of the findings from clinical studies and pharmacokinetic analyses of the antiviral agent valganciclovir for dosing of the drug to prevent cytomegalovirus (CMV) disease in solid organ transplant recipients are reviewed.
SUMMARY
Valganciclovir, an oral prodrug of ganciclovir, is as effective as oral ganciclovir for preventing CMV disease, although prophylaxis with either agent may delay CMV disease. Dosage reduction is required for both drugs in patients with renal impairment to prevent high plasma ganciclovir concentrations and toxicity. A valganciclovir dosage of 900 mg/day is required in patients with normal renal function, especially those at high risk for CMV disease, to provide adequate systemic ganciclovir exposure. Some studies suggest that a lower dosage might suffice for patients at a low risk for CMV disease.
CONCLUSION
Valganciclovir dosing should be based on renal function to avoid toxicity.
Topics: Antibiotic Prophylaxis; Antiviral Agents; Cytomegalovirus Infections; Ganciclovir; Humans; Lung Transplantation; Organ Transplantation; Valganciclovir
PubMed: 16990640
DOI: 10.2146/ajhp060379 -
Molecules (Basel, Switzerland) Nov 2022Qingdai-Mabo (QM), a traditional Chinese herbal formula composed of medicinal herb and fungus, has been used for treatment of cough and viral pneumonia. However, the...
Qingdai-Mabo (QM), a traditional Chinese herbal formula composed of medicinal herb and fungus, has been used for treatment of cough and viral pneumonia. However, the underlying mechanism and bioactive components against anti-influenza A virus remain unclear. In the present study, ethyl acetate (EA) extract of QM decoctions was tested for its biological activity against acute lung injury (ALI) and its main components were identified using UPLC-MS/MS. In total, 18 bioactive components were identified, including 2-Methylquinaozlin-4(3H)-one (C1), which showed significant antiviral activity in vitro with an IC of 23.8 μg/mL. Furthermore, we validated the efficacy of C1 in ameliorating ALI lesions and inflammation in influenza A virus-infected mice. The results showed that C1 significantly reduced the lung index, downregulated neuraminidase (NA) and nucleoprotein (NP), and decreased the expression of pro-inflammatory molecules IFN-α, TNF-α, MCP-1, IL-6, and IL-8; however, they enhanced levels of IL-10 and IFN-γ in lung homogenate from mice infected by influenza A virus. In addition, C1 inhibited the recruitment of macrophages. These in vitro and in vivo studies suggested that the significant anti-influenza A virus activity contributed to its curative effect on lesions and inflammation of viral pneumonia in mice. Given its potential antiviral activity against influenza A virus, C1 is determined to be a main active component in the EA extract of QM. Taken together, the antiviral activity of C1 suggests its potential as an effective treatment against viral pneumonia via the inhibition of virus replication, but the mechanism C1 on antiviral research needs to be explored further.
Topics: Mice; Animals; Influenza A virus; Antiviral Agents; Influenza A Virus, H1N1 Subtype; Chromatography, Liquid; Tandem Mass Spectrometry; Acute Lung Injury; Inflammation; Pneumonia, Viral; Plant Extracts
PubMed: 36431955
DOI: 10.3390/molecules27227857