scholarly journals Anti-Adenovirus Activity of the Medical Intranasal Drug Nazoferon

2021 ◽  
Vol 83 (2) ◽  
pp. 73-81
Author(s):  
O.Yu. Povnitsa ◽  
◽  
L.O. Biliavska ◽  
Yu.B. Pankivska ◽  
S.D. Zagorodnya ◽  
...  
Keyword(s):  
Respiratory Infections ◽  
Low Cost ◽  
Rapid Development ◽  
Colorimetric Method ◽  
Antiviral Drug ◽  
Human Adenovirus ◽  
Human Adenoviruses ◽  
Direct Acting Antiviral ◽  
Optimal Drug

Currently, 90 different types of human adenoviruses (HAdV) are known, which have been classified into seven species from A to G and new adenovirus types continue to emerge. Antigenic diversity of viruses inhibits the process of creating universal vaccines and causes the development of resistance to direct-acting antiviral drugs. In addition to the rapid development of drug resistance, too narrow a range of existing drugs and a significant number of side effects limits the treatment of adenoviral infections. There is currently no specific etiotropic antiviral drug. Therefore, the development of new effective drugs and the selection of the optimal drug for the treatment of infections caused by adenoviruses remain relevant. The aim of the study was to investigate the antiviral properties of the drugs Nazoferon spray and Nazoferon drops in a model of human adenovirus serotype 3. Methods. Determination of cytotoxicity and antiviral action of drugs was performed by standard colorimetric method using MTT. The titer of the virus, synthesized in the presence of drugs was determined by the end point of dilution of the virus, which causes 50% development of the cytopathic effect of the virus on cells (СPE). Results. Low cytotoxicity of Nazoferon spray and Nazoferon drops (manufactured by JSC Farmak, Ukraine) was shown, CC50 is 53854 IU/ml and 54357 IU/ml, respectively. Quantitative and qualitative composition of excipients had no cytotoxic effect. In prophylactic regimens, interferon preparations did not inhibit the reproduction of adenovirus in vitro. Taking into account that most of the virions remain associated with the cells during the reproduction of adenovirus in the cell, we used test to determine infectivity lysates of infected and treated cells. The infectious titer of the synthesized HAdV3 was reduced by 3.2 log10 and 3.7 log10 for Nazoferon spray and drops, respectively. Conclusions. Nazoferon spray and drops can be recommended as anti-adenoviral drugs that block the reproduction of adenovirus, and due to their bioavailability and low cost have significant advantages in the treatment of acute respiratory infections (ARIs) caused by human adenoviruses.

scholarly journals IDentif.AI: Artificial Intelligence Pinpoints Remdesivir in Combination with Ritonavir and Lopinavir as an Optimal Regimen Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

2020 ◽  
Author(s):  
Agata Blasiak ◽  
Jhin Jieh Lim ◽  
Shirley Gek Kheng Seah ◽  
Theodore Kee ◽  
Alexandria Remus ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Severe Acute Respiratory Syndrome ◽  
Combination Therapy ◽  
Rapid Development ◽  
Drug Combinations ◽  
Drug Candidate ◽  
Optimal Drug ◽  
Order Of Magnitude ◽  
Drug Regimens

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) has led to the rapid initiation of urgently needed clinical trials of repurposed drug combinations and monotherapies. These regimens were primarily relying on mechanism-of-action based selection of drugs, many of which have yielded positive in vitro but largely negative clinical outcomes. To overcome this challenge, we report the use of IDentif.AI, a platform that rapidly optimizes infectious disease (ID) combination therapy design using artificial intelligence (AI). In this study, IDentif.AI was implemented on a 12-drug candidate therapy search set representing over 530,000 possible drug combinations. IDentif.AI demonstrated that the optimal combination therapy against SARS-CoV-2 was comprised of remdesivir, ritonavir, and lopinavir, which mediated a 6.5-fold improvement in efficacy over remdesivir alone. Additionally, IDentif.AI showed hydroxychloroquine and azithromycin to be relatively ineffective. The identification of a clinically actionable optimal drug combination was completed within two weeks, with a 3-order of magnitude reduction in the number of tests typically needed. IDentif.AI analysis was also able to independently confirm clinical trial outcomes to date without requiring any data from these trials. The robustness of the IDentif.AI platform suggests that it may be applicable towards rapid development of optimal drug regimens to address current and future outbreaks.

scholarly journals A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19

2021 ◽  
Author(s):  
Maren de Vries ◽  
Adil S. Mohamed ◽  
Rachel A. Prescott ◽  
Ana M. Valero-Jimenez ◽  
Ludovic Desvignes ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Life Cycle ◽  
Comparative Analysis ◽  
Airway Epithelium ◽  
Antiviral Drug ◽  
Viral Polymerase ◽  
Direct Acting Antiviral ◽  
Polymerase Inhibitor ◽  
Direct Acting

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of Coronavirus Disease 2019 (COVID-19). There is a dire need for novel effective antivirals to treat COVID-19, as the only approved direct-acting antiviral to date is remdesivir, targeting the viral polymerase complex. A potential alternate target in the viral life cycle is the main SARS-CoV-2 protease 3CLpro (Mpro). The drug candidate PF-00835231 is the active compound of the first anti-3CLpro regimen in clinical trials. Here, we perform a comparative analysis of PF-00835231, the pre-clinical 3CLpro inhibitor GC-376, and the polymerase inhibitor remdesivir, in alveolar basal epithelial cells modified to express ACE2 (A549+ACE2 cells). We find PF-00835231 with at least similar or higher potency than remdesivir or GC-376. A time-of-drug-addition approach delineates the timing of early SARS-CoV-2 life cycle steps in A549+ACE2 cells and validates PF-00835231’s early time of action. In a model of the human polarized airway epithelium, both PF-00835231 and remdesivir potently inhibit SARS-CoV-2 at low micromolar concentrations. Finally, we show that the efflux transporter P-glycoprotein, which was previously suggested to diminish PF-00835231’s efficacy based on experiments in monkey kidney Vero E6 cells, does not negatively impact PF-00835231 efficacy in either A549+ACE2 cells or human polarized airway epithelial cultures. Thus, our study provides in vitro evidence for the potential of PF-00835231 as an effective SARS-CoV-2 antiviral and addresses concerns that emerged based on prior studies in non-human in vitro models. Importance: The arsenal of SARS-CoV-2 specific antiviral drugs is extremely limited. Only one direct-acting antiviral drug is currently approved, the viral polymerase inhibitor remdesivir, and it has limited efficacy. Thus, there is a substantial need to develop additional antiviral compounds with minimal side effects and alternate viral targets. One such alternate target is its main protease, 3CLpro (Mpro), an essential component of the SARS-CoV-2 life cycle processing the viral polyprotein into the components of the viral polymerase complex. In this study, we characterize a novel antiviral drug, PF-00835231, which is the active component of the first-in-class 3CLpro-targeting regimen in clinical trials. Using 3D in vitro models of the human airway epithelium, we demonstrate the antiviral potential of PF-00835231 for inhibition of SARS-CoV-2.

scholarly journals Identification, isolation, structural characterization, in silico toxicity prediction and in vitro cytotoxicity assay of simeprevir acidic and oxidative degradation products

RSC Advances ◽  
2020 ◽  
Vol 10 (70) ◽  
pp. 42816-42826
Author(s):  
Rasha M. Ahmed ◽  
Marwa A. A. Fayed ◽  
Mohammed F. El-Behairy ◽  
Inas A. Abdallah
Keyword(s):  
Chronic Hepatitis ◽  
Degradation Products ◽  
Antiviral Drug ◽  
Oxidative Degradation ◽  
In Vitro Cytotoxicity ◽  
Toxicity Prediction ◽  
Direct Acting Antiviral ◽  
In Silico Toxicity ◽  
Direct Acting

Simeprevir is a new direct-acting antiviral drug used for the treatment of chronic hepatitis C.

scholarly journals A low-cost method to test cytotoxic effects of Crotalus vegrandis (Serpentes: Viperidae) venom on kidney cell cultures

2005 ◽  
Vol 47 (3) ◽  
pp. 147-152 ◽  
Author(s):  
María E. Girón ◽  
Irma Aguilar ◽  
Lisandro Romero ◽  
Elda E. Sánchez ◽  
John c. Pérez ◽  
...  
Keyword(s):  
Cell Culture ◽  
Cell Cultures ◽  
Renal Cortex ◽  
Smooth Muscle Actin ◽  
Low Cost ◽  
Colorimetric Method ◽  
Vero Cells ◽  
Renal Lesion ◽  
Crude Venom

The pathogenesis of the renal lesion upon envenomation by snakebite has been related to myolysis, hemolysis, hypotension and/or direct venom nephrotoxicity caused by the venom. Both primary and continuous cell culture systems provide an in vitro alternative for quantitative evaluation of the toxicity of snake venoms. Crude Crotalus vegrandis venom was fractionated by molecular exclusion chromatography. The toxicity of C. vegrandis crude venom, hemorrhagic, and neurotoxic fractions were evaluated on mouse primary renal cells and a continuous cell line of Vero cells maintained in vitro. Cells were isolated from murine renal cortex and were grown in 96 well plates with Dulbecco's Modified Essential Medium (DMEM) and challenged with crude and venom fractions. The murine renal cortex cells exhibited epithelial morphology and the majority showed smooth muscle actin determined by immune-staining. The cytotoxicity was evaluated by the tetrazolium colorimetric method. Cell viability was less for crude venom, followed by the hemorrhagic and neurotoxic fractions with a CT50 of 4.93, 18.41 and 50.22 µg/mL, respectively. The Vero cell cultures seemed to be more sensitive with a CT50 of 2.9 and 1.4 µg/mL for crude venom and the hemorrhagic peak, respectively. The results of this study show the potential of using cell culture system to evaluate venom toxicity.

scholarly journals EFFICACY OF KAGOCEL IN NONSPECIFIC PREVENTION OF ACUTE RESPIRATORY VIRAL INFECTIONS AND INFLUENZA

2019 ◽  
Vol 5 (3) ◽  
pp. 68-76
Author(s):  
Irina V. Ozerova ◽  
Nikolay A. Malishev
Keyword(s):  
Immune Response ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Antiviral Drug ◽  
Economic Cost ◽  
Antiviral Drugs ◽  
High Risk Group ◽  
Time Data ◽  
Direct Acting Antiviral ◽  
Respiratory Viral Infections

Acute respiratory viral infections (ARVI) are some of the most widely spread diseases worldwide that are of 80% of economic cost of infectious diseases. It is known that specific prophylaxis (vaccination) and, in some clinical cases, direct-acting antiviral prophylaxis are key strategies for the prevention of influenza as one of the most dangerous ARVI viruses. However, there are a number of reasons why specific prophylaxis of influenza does not entirely address the issue of prophylaxis of ARVI that are caused by more than 200 different viruses, such as formation of immune response only to vaccine influenza strains and absence of immune response to other respiratory infections, induction in the case of short-term protection, especially, in the aged and others. Prevention of influenza with antiviral drugs is limited by risks of development of resistant influenza strains aa well as contraindications and limitations of use. Therefore, the use of nonspecific drugs such as broad-spectrum antiviral drugs of interferon type (IFN) and their inducers (II), as well as sanitary and hygienic measures is recommended for prevention. For the purpose of prevention, the use of inducers of endogenic interferons is relevant in unvaccinated persons during pre-epidemic and epidemic ARVI periods; in high-risk group (students, medical professions, transport workers, elderly, patients with comorbid pathologies, people in structured organizations, for example, military personnel), in immunocompromised people. One of the most extensively studied interferon inducers widely used in clinical practice since 2003 for prevention and treatment of influenza and diseases caused by Herpesviruses is an antiviral drug Kagocel®. The paper presents real-time data of the preventive efficacy of Kagocel® in the therapy of acute respiratory viral infections and influenza caused by different viral strains including pandemic ones.

scholarly journals Discovery of direct-acting antiviral agents with a graphene-based fluorescent nanosensor

2020 ◽  
Vol 6 (22) ◽  
pp. eaaz8201 ◽  
Author(s):  
Se-Jin Park ◽  
Jungho Kim ◽  
Seounghun Kang ◽  
Hyung Jin Cha ◽  
Hojeong Shin ◽  
...  
Keyword(s):  
Rna Virus ◽  
Antiviral Drug ◽  
Oxide System ◽  
Chemical Screening ◽  
Drug Candidates ◽  
Direct Acting Antiviral ◽  
Biosensor System ◽  
Direct Acting

Direct-acting agents against viral components are considered as the most promising candidates for the successful antiviral therapeutics. To date, no direct-acting drugs exist for the treatment against dengue virus (DV) infection, which can develop into life-threatening diseases. RNA-dependent RNA polymerase (RdRp), an RNA virus–specific enzyme highly conserved among various viral families, has been known as the broad-range antiviral drug target. Here, we developed an RNA-based graphene biosensor system [RNA nano-graphene oxide system (RANGO)] to enable the fluorescence-based quantitative analysis of the RdRp enzyme activity. We used the RANGO system to a high-throughput chemical screening to identify novel direct-acting antiviral drug candidates targeting DV RdRp from the FDA-approved small-molecule library. RANGO accelerated the massive selection of drug candidates. We found that one of the selected hit compounds, montelukast, showed antiviral activity in vitro and in vivo by directly inhibiting replication of DV and thus relieved related symptoms.

scholarly journals In Vitro Evaluation of the Antiviral Activity of Methylene Blue Alone or in Combination against SARS-CoV-2

2021 ◽  
Vol 10 (14) ◽  
pp. 3007
Author(s):  
Mathieu Gendrot ◽  
Priscilla Jardot ◽  
Océane Delandre ◽  
Manon Boxberger ◽  
Julien Andreani ◽  
...  
Keyword(s):  
Methylene Blue ◽  
Antiviral Activity ◽  
Viral Entry ◽  
Low Cost ◽  
Antiviral Drug ◽  
Effective Concentration ◽  
Rt Pcr ◽  
Post Entry ◽  
Median Effective Concentration

A new severe acute respiratory syndrome coronavirus (SARS-CoV-2) causing coronavirus diseases 2019 (COVID-19), which emerged in Wuhan, China in December 2019, has spread worldwide. Currently, very few treatments are officially recommended against SARS-CoV-2. Identifying effective, low-cost antiviral drugs with limited side effects that are affordable immediately is urgently needed. Methylene blue, a synthesized thiazine dye, may be a potential antiviral drug. Antiviral activity of methylene blue used alone or in combination with several antimalarial drugs or remdesivir was assessed against infected Vero E6 cells infected with two clinically isolated SARS-CoV-2 strains (IHUMI-3 and IHUMI-6). Effects both on viral entry in the cell and on post-entry were also investigated. After 48 h post-infection, the viral replication was estimated by RT-PCR. The median effective concentration (EC50) and 90% effective concentration (EC90) of methylene blue against IHUMI-3 were 0.41 ± 0.34 µM and 1.85 ± 1.41 µM, respectively; 1.06 ± 0.46 µM and 5.68 ± 1.83 µM against IHUMI-6. Methylene blue interacted at both entry and post-entry stages of SARS-CoV-2 infection in Vero E6 cells as retrieved for hydroxychloroquine. The effects of methylene blue were additive with those of quinine, mefloquine and pyronaridine. The combinations of methylene blue with chloroquine, hydroxychloroquine, desethylamodiaquine, piperaquine, lumefantrine, ferroquine, dihydroartemisinin and remdesivir were antagonist. These results support the potential interest of methylene blue to treat COVID-19.

Adipogenic potential of multiple human adenoviruses in vivo and in vitro in animals

2006 ◽  
Vol 290 (1) ◽  
pp. R190-R194 ◽  
Author(s):  
Leah D. Whigham ◽  
Barbara A. Israel ◽  
Richard L. Atkinson
Keyword(s):  
Food Intake ◽  
Serum Cholesterol ◽  
Visceral Fat ◽  
Serum Lipids ◽  
Adipocyte Differentiation ◽  
Human Adenovirus ◽  
In Vitro Assays ◽  
Human Adenoviruses ◽  
Triglyceride Accumulation

Human adenovirus-36 (Ad-36) increases adiposity in chickens, mice, and nonhuman primates and is associated with human obesity. Ad-36 paradoxically reduces serum cholesterol and triglycerides in animal models. Ad-36 increases adipocyte differentiation and triglyceride accumulation in 3T3-L1 cells in vitro. This study evaluated whether three other human adenoviruses increase adiposity in chickens and in 3T3-L1 cells in vitro. We inoculated chickens with human Ad-2, Ad-31, Ad-37, or media at age 3 wk. Food intake and weights were recorded for 3.5 wk, and then chickens were killed and visceral fat, body composition, serum lipids, and viral antibody status were determined. Visceral fat and total body fat were significantly elevated ( P < 0.001) in the Ad-37 group compared with all other groups. Final body weights were higher in chickens inoculated with Ad-37 compared with Ad-2, but not significantly higher than in control or Ad-31 groups. Food intake did not differ among groups. Serum cholesterol was elevated in Ad-37 chickens compared with control ( P < 0.01) but was not affected by other viruses. Triglycerides were reduced in Ad-37 chickens ( P < 0.0001) but were not affected by other viruses. In 3T3-L1 cells in vitro, Ad-31, Ad-36, and Ad-37, but not Ad-2, increased adipocyte differentiation and triglycerides accumulation. In summary, Ad-37 is another human adenovirus that increases adiposity and reduces serum triglycerides in an animal model. However, the response of serum cholesterol is opposite that of Ad-36. Evaluation of other human adenoviruses to determine their effects on adiposity and serum lipids is warranted, but in vitro assays may not be definitive for this purpose.

scholarly journals Filociclovir Is a Potent In Vitro and In Vivo Inhibitor of Human Adenoviruses

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Karoly Toth ◽  
Islam T. M. Hussein ◽  
Ann E. Tollefson ◽  
Baoling Ying ◽  
Jacqueline F. Spencer ◽  
...  
Keyword(s):  
Body Weight ◽  
Virus Replication ◽  
Antiviral Drug ◽  
Clinical Manifestations ◽  
Body Weight Loss ◽  
Human Adenovirus ◽  
Clinical Safety ◽  
Virus Challenge

ABSTRACT Human adenovirus (HAdV) infection is common in the general population and can cause a range of clinical manifestations, among which pneumonia and keratoconjunctivitis are the most common. Although HAdV infections are mostly self-limiting, infections in immunocompromised individuals can be severe. No antiviral drug has been approved for treating adenoviruses. Filociclovir (FCV) is a nucleoside analogue which has successfully completed phase I human clinical safety studies and is now being developed for treatment of human cytomegalovirus (HCMV)-related disease in immunocompromised patients. In this report, we show that FCV is a potent broad-spectrum inhibitor of HAdV types 4 to 8, with 50% effective concentrations (EC50s) ranging between 1.24 and 3.6 μM and a 50% cytotoxic concentration (CC50) of 100 to 150 μM in human foreskin fibroblasts (HFFs). We also show that the prophylactic oral administration of FCV (10 mg/kg of body weight) 1 day prior to virus challenge and then daily for 14 days to immunosuppressed Syrian hamsters infected intravenously with HAdV6 was sufficient to prevent morbidity and mortality. FCV also mitigated tissue damage and inhibited virus replication in the liver. The 10-mg/kg dose had similar effects even when the treatment was started on day 4 after virus challenge. Furthermore, FCV administered at the same dose after intranasal challenge with HAdV6 partially mitigated body weight loss but significantly reduced pathology and virus replication in the lung. These findings suggest that FCV could potentially be developed as a pan-adenoviral inhibitor.

scholarly journals In Silico Designing of a Multi-Epitope Based Vaccine Candidate Against Human Adenovirus Type B3 Respiratory Infections by Utilising Various Immunoinformatics Approaches

2021 ◽  
Vol 29 (1) ◽  
Author(s):  
Somnath Panda ◽  
Urmila Banik ◽  
Arun Kumar Adhikary
Keyword(s):  
Molecular Docking ◽  
Physicochemical Properties ◽  
In Silico ◽  
Vaccine Development ◽  
Vaccine Candidate ◽  
Respiratory Infections ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Conventional Vaccine

Human adenovirus type B3 (HAdV-B3) causes severe respiratory infections, hence an efficient vaccine is required. Unfortunately, the presence of numerous hexon variations makes conventional vaccine designing difficult which warrants an alternative method. Therefore, an in silico multi-epitope vaccine had been constructed against appropriate hexon variants of HAdV-B3. The allergenicity, antigenicity, structure, physicochemical properties along with molecular docking with TLR-3 and TLR-9 had also been predicted. The constructed vaccine had 23 different epitopes. It showed non-allergic but antigenic nature with 30hours of half-life in vitro and exhibited thermostable nature. We anticipate that this will considerably reduce the time and expense of biological work needed for future vaccine development.

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