Liposomal Systems as Nanocarriers for the Antiviral Agent Ivermectin

International Journal of Biomaterials ◽

10.1155/2016/8043983 ◽

2016 ◽

Vol 2016 ◽

pp. 1-15 ◽

Cited By ~ 11

Author(s):

Romina Croci ◽

Elisabetta Bottaro ◽

Kitti Wing Ki Chan ◽

Satoru Watanabe ◽

Margherita Pezzullo ◽

...

Keyword(s):

Yellow Fever ◽

Rna Virus ◽

Multiorgan Failure ◽

Antiviral Agent ◽

Drug Carriers ◽

Virus Infections ◽

Starting Point ◽

Significant Public Health ◽

High Cytotoxicity

RNA virus infections can lead to the onset of severe diseases such as fever with haemorrhage, multiorgan failure, and mortality. The emergence and reemergence of RNA viruses continue to pose a significant public health threat worldwide with particular attention to the increasing incidence of flaviviruses, among others Dengue, West Nile Virus, and Yellow Fever viruses. Development of new and potent antivirals is thus urgently needed. Ivermectin, an already known antihelminthic drug, has shown potent effectsin vitroonFlavivirushelicase, with EC50values in the subnanomolar range for Yellow Fever and submicromolar EC50for Dengue Fever, Japanese encephalitis, and tick-borne encephalitis viruses. However ivermectin is hampered in its application by pharmacokinetic problems (little solubility and high cytotoxicity). To overcome such problems we engineered different compositions of liposomes as ivermectin carriers characterizing and testing them on several cell lines for cytotoxicity. The engineered liposomes were less cytotoxic than ivermectin alone and they showed a significant increase of the antiviral activity in all the Dengue stains tested (1, 2, and S221). In the current study ivermectin is confirmed to be an effective potential antiviral and liposomes, as drug carriers, are shown to modulate the drug activity. All together the results represent a promising starting point for future improvement of ivermectin as antiviral and its delivery.

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Ebola Virus ? A Global Threat

Journal of Enam Medical College ◽

10.3329/jemc.v5i1.21497 ◽

2015 ◽

Vol 5 (1) ◽

pp. 44-51

Author(s):

Mejbah Uddin Ahmed ◽

Sushmita Roy

Keyword(s):

Nonhuman Primates ◽

Ebola Virus ◽

Rna Virus ◽

Close Contact ◽

Multiorgan Failure ◽

Hemorrhagic Fever ◽

Human Infection ◽

Current Data ◽

Sub Saharan Africa ◽

Virus Infections

Ebola virus is a filamentous, enveloped, non-segmented, single-stranded, negative-sense RNA virus. It belongs to the Filoviridae and was first recognized near the Ebola River valley in Zaire in 1976. Since then most of the outbreaks have occurred to both human and nonhuman primates in sub-Saharan Africa. Ebola virus causes highly fatal hemorrhagic fever in human and nonhuman primates. In addition to hemorrhagic fever, it could be used as a bioterrorism agent. Although its natural reservoir is yet to be proven, current data suggest that fruit bats are the possibility. Infection has also been documented through the handling of infected chimpanzees, gorillas, monkeys, forest antelope and porcupines. Human infection is caused through close contact with the blood, secretion, organ or other body fluids of infected animal. Human-to-human transmission is also possible. Ebola virus infections are characterized by immune suppression and a systemic inflammatory response that causes impairment of the vascular, coagulation, and immune systems, leading to multiorgan failure and shock. The virus constitutes an important public health threat in Africa and also worldwide as no effective treatment or vaccine is available till now DOI: http://dx.doi.org/10.3329/jemc.v5i1.21497 J Enam Med Col 2015; 5(1): 44-51

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In vitro validation of camphene as a potential antiviral agent against betanodavirus causing viral nervous necrosis in barramundi

Anti-Infective Agents ◽

10.2174/2211352519999210111223529 ◽

2021 ◽

Vol 19 ◽

Author(s):

Ruby Singh ◽

Prachi Srivastava ◽

Deepika Anand ◽

Pani K. Prasad

Keyword(s):

Mtt Assay ◽

Viral Infections ◽

Rna Virus ◽

Antiviral Agent ◽

Sea Bass ◽

Viral Nervous Necrosis ◽

Cytotoxicity Studies ◽

In Silico Studies ◽

Juvenile Stages

Introduction:: Viral infections are major threat to aquaculture industry throughout the world. Betanodavirus is one of the most infectious virus that causes highest mortality in larval and juvenile stages of Lates calcarifer commonly known as Barramundi. Methods:: Methods: It is a single stranded positive sense RNA virus and causes viral nervous necrosis (VNN). VNN is caused by RNA virus which gets transmitted both horizontally and vertically so the most effective method against this virus is to vaccinate the fish, however vaccination becomes difficult since the disease is associated with the outbreaks in larval and juvenile stages which are not that much immunocompetent. In our previous in silico studies we proved the stability of camphene as a better phytochemical agent. Results:: In continuation to prove the authenticity of Camphene as potential antiviral agent against betanodavirus, its in vitro validation was performed. Sea bass kidney cell line (SISK) was selected for carrying out the in vitro studies and cytotoxicity studies of Camphene in the SISK was was done by MTT assay. Based on the analysis of MTT assay different dosage of camphene were selected viz.,(0.2, 0.5, 1, 1.5, 2, 2.5, 5, 10, 20, 30 μg/ml). The SISK cells were infected with virus inoculum (200μl). Further the antiviral activity of Camphene on infected SISK cells by Betanodavirus was elucidated with the help of quantitative Real time PCR(qPCR) on the 3rd and 5th day of infection. Conclusion:: Analysis of results depictecd that the dose of camphene 2 to 10 μg/ml is the safest dose against Betanodavirus. Hence this is aptly revealed that camphene can be used as potential antiviral agent against Betanodavirus.

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Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections

Molecules ◽

10.3390/molecules25204813 ◽

2020 ◽

Vol 25 (20) ◽

pp. 4813

Author(s):

Marcella Bassetto ◽

Cecilia M. Cima ◽

Mattia Basso ◽

Martina Salerno ◽

Frank Schwarze ◽

...

Keyword(s):

Zika Virus ◽

Antiviral Agents ◽

Antiviral Agent ◽

Antiviral Effect ◽

Health Concern ◽

Virus Infections ◽

Direct Acting Antiviral ◽

Direct Acting ◽

Further Development

Previously considered a neglected flavivirus, Zika virus has recently emerged as a public health concern due to its ability to spread rapidly and cause severe neurological disorders, such as microcephaly in newborn babies from infected mothers, and Guillain-Barré syndrome in adults. Despite extensive efforts towards the identification of effective therapies, specific antivirals are still not available. As part of ongoing medicinal chemistry studies to identify new antiviral agents, we screened against Zika virus replication in vitro in a targeted internal library of small-molecule agents, comprising both nucleoside and non-nucleoside agents. Among the compounds evaluated, novel aryloxyphosphoramidate prodrugs of the nucleosides 2′-C-methyl-adenosine, 2-CMA, and 7-deaza-2′C-methyl-adenosine, 7-DMA, were found to significantly inhibit the virus-induced cytopathic effect in multiple relevant cell lines. In addition, one of these prodrugs exhibits a synergistic antiviral effect against Zika virus when applied in combination with an indirect antiviral agent, a l-dideoxy bicyclic pyrimidine nucleoside analogue, which potently inhibits vaccinia and measles viruses in vitro by targeting a host pathway. Our findings provide a solid basis for further development of an antiviral therapy for Zika virus infections, possibly exploiting a dual approach combining two different agents, one targeting the viral polymerase (direct-acting antiviral), the second targeting a host-directed autophagy mechanism.

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4'-Fluorouridine is a broad-spectrum orally efficacious antiviral blocking respiratory syncytial virus and SARS-CoV-2 replication

10.1101/2021.05.19.444875 ◽

2021 ◽

Author(s):

Julien Sourimant ◽

Carolin Lieber ◽

Megha Aggarwal ◽

Robert Cox ◽

Josef Wolf ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Broad Spectrum ◽

Rna Virus ◽

Oral Treatment ◽

The Elderly ◽

Virus Infections ◽

Once Daily ◽

Syncytial Virus ◽

Well Differentiated

The COVID-19 pandemic has underscored the critical need for broad-spectrum therapeutics against respiratory viruses. Respiratory syncytial virus (RSV) is a major threat to pediatric patients and the elderly. We describe 4'-fluorouridine (4'-FlU, EIDD-2749), a ribonucleoside analog that inhibits RSV, related RNA viruses, and SARS-CoV-2 with high selectivity index in cells and well-differentiated human airway epithelia. Polymerase inhibition in in vitro RdRP assays established for RSV and SARS-CoV-2 revealed transcriptional pauses at positions i or i+3/4 post-incorporation. Once-daily oral treatment was highly efficacious at 5 mg/kg in RSV-infected mice or 20 mg/kg in ferrets infected with SARS-CoV-2 WA1/2020 or variant-of-concern (VoC) isolate CA/2020, initiated 24 or 12 hours after infection, respectively. These properties define 4'-FlU as a broad-spectrum candidate for the treatment of RSV, SARS-CoV-2 and related RNA virus infections.

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Infectious RNA transcribed in vitro from a cDNA copy of the human coronavirus genome cloned in vaccinia virus

Journal of General Virology ◽

10.1099/0022-1317-82-6-1273 ◽

2001 ◽

Vol 82 (6) ◽

pp. 1273-1281 ◽

Cited By ~ 165

Author(s):

Volker Thiel ◽

Jens Herold ◽

Barbara Schelle ◽

Stuart G. Siddell

Keyword(s):

Vaccinia Virus ◽

Rna Virus ◽

Genetic System ◽

Reverse Genetic System ◽

Human Coronavirus ◽

Cdna Copy ◽

Starting Point ◽

Positive Strand Rna ◽

Virus Genomes

The coronavirus genome is a positive-strand RNA of extraordinary size and complexity. It is composed of approximately 30000 nucleotides and it is the largest known autonomously replicating RNA. It is also remarkable in that more than two-thirds of the genome is devoted to encoding proteins involved in the replication and transcription of viral RNA. Here, a reverse-genetic system is described for the generation of recombinant coronaviruses. This system is based upon the in vitro transcription of infectious RNA from a cDNA copy of the human coronavirus 229E genome that has been cloned and propagated in vaccinia virus. This system is expected to provide new insights into the molecular biology and pathogenesis of coronaviruses and to serve as a paradigm for the genetic analysis of large RNA virus genomes. It also provides a starting point for the development of a new class of eukaryotic, multi-gene RNA vectors that are able to express several proteins simultaneously.

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IMPACT OF SORBITOL- INDUCED OSMOTIC STRESS ON SOME BIOCHEMICAL TRAITS OF POTATO IN VITRO

IRAQI JOURNAL OF AGRICULTURAL SCIENCES ◽

10.36103/ijas.v51i4.1082 ◽

2020 ◽

Vol 51 (4) ◽

pp. 1038-1047

Author(s):

Mawia & et al.

Keyword(s):

Ascorbic Acid ◽

Osmotic Stress ◽

Cytoplasmic Membrane ◽

Genotypic Variation ◽

Membrane Damage ◽

Membrane Integrity ◽

Culture Collection ◽

Nutritive Medium ◽

Starting Point

This study had as principal objective identification of osmotic-tolerant potato genotypes by using "in vitro" tissue culture and sorbitol as a stimulating agent, to induce water stress, which was added to the culture nutritive medium in different concentration (0,50, 110, 220, 330 and 440 mM). The starting point was represented by plantlets culture collection, belonging to eleven potato genotypes: Barcelona, Nectar, Alison, Jelly, Malice, Nazca, Toronto, Farida, Fabulla, Colomba and Spunta. Plantlets were multiplied between two internodes to obtain microcuttings (in sterile condition), which were inoculated on medium. Sorbitol-induced osmotic stress caused a significant reduction in the ascorbic acid, while the concentration of proline, H2O2 and solutes leakage increased compared with the control. Increased the proline content prevented lipid peroxidation, which played a pivotal role in the maintenance of membrane integrity under osmotic stress conditions. The extent of the cytoplasmic membrane damage depends on osmotic stress severity and the genotypic variation in the maintenance of membranes stability was highly associated with the ability of producing more amounts of osmoprotectants (proline) and the non-enzymic antioxidant ascorbic acid in response to osmotic stress level. The results showed that the genotypes Jelly, Nectar, Allison, Toronto, and Colomba are classified as highly osmotic stress tolerant genotypes, while the genotypes Nazca and Farida are classified as osmotic stress susceptible ones.

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Enzyme Promiscuous Activity: How to Define it and its Evolutionary Aspects

Protein and Peptide Letters ◽

10.2174/0929866527666191223141205 ◽

2020 ◽

Vol 27 (5) ◽

pp. 400-410

Author(s):

Valentina De Luca ◽

Luigi Mandrich

Keyword(s):

Gene Evolution ◽

Sequence Divergence ◽

High Specificity ◽

Industrial Applications ◽

Point Of View ◽

Enzyme Promiscuity ◽

Primary Activity ◽

Starting Point ◽

Main Activity

: Enzymes are among the most studied biological molecules because better understanding enzymes structure and activity will shed more light on their biological processes and regulation; from a biotechnological point of view there are many examples of enzymes used with the aim to obtain new products and/or to make industrial processes less invasive towards the environment. Enzymes are known for their high specificity in the recognition of a substrate but considering the particular features of an increasing number of enzymes this is not completely true, in fact, many enzymes are active on different substrates: this ability is called enzyme promiscuity. Usually, promiscuous activities have significantly lower kinetic parameters than to that of primary activity, but they have a crucial role in gene evolution. It is accepted that gene duplication followed by sequence divergence is considered a key evolutionary mechanism to generate new enzyme functions. In this way, promiscuous activities are the starting point to increase a secondary activity in the main activity and then get a new enzyme. The primary activity can be lost or reduced to a promiscuous activity. In this review we describe the differences between substrate and enzyme promiscuity, and its rule in gene evolution. From a practical point of view the knowledge of promiscuity can facilitate the in vitro progress of proteins engineering, both for biomedical and industrial applications. In particular, we report cases regarding esterases, phosphotriesterases and cytochrome P450.

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Biological and In silico Studies on Synthetic Analogues of Tyrosine Betaine as Inhibitors of Neprilysin - A Drug Target for the Treatment of Heart Failure

Current Pharmaceutical Design ◽

10.2174/1381612824666180515114236 ◽

2018 ◽

Vol 24 (17) ◽

pp. 1899-1904

Author(s):

Daniel Fabio Kawano ◽

Marcelo Rodrigues de Carvalho ◽

Mauricio Ferreira Marcondes Machado ◽

Adriana Karaoglanovic Carmona ◽

Gilberto Ubida Leite Braga ◽

...

Keyword(s):

Heart Failure ◽

Secondary Metabolites ◽

Structural Similarity ◽

Structural Features ◽

Major Constituent ◽

Binding Modes ◽

Starting Point ◽

In Silico Studies ◽

Nep Inhibition

Background: Fungal secondary metabolites are important sources for the discovery of new pharmaceuticals, as exemplified by penicillin, lovastatin and cyclosporine. Searching for secondary metabolites of the fungi Metarhizium spp., we previously identified tyrosine betaine as a major constituent. Methods: Because of the structural similarity with other inhibitors of neprilysin (NEP), an enzyme explored for the treatment of heart failure, we devised the synthesis of tyrosine betaine and three analogues to be subjected to in vitro NEP inhibition assays and to molecular modeling studies. Results: In spite of the similar binding modes with other NEP inhibitors, these compounds only displayed moderate inhibitory activities (IC50 ranging from 170.0 to 52.9 µM). However, they enclose structural features required to hinder passive blood brain barrier permeation (BBB). Conclusions: Tyrosine betaine remains as a starting point for the development of NEP inhibitors because of the low probability of BBB permeation and, consequently, of NEP inhibition at the Central Nervous System, which is associated to an increment in the Aβ levels and, accordingly, with a higher risk for the onset of Alzheimer's disease.

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Hybrid Design of Isonicotinic Acid Hydrazide Derivatives: Machine Learning Studies, Synthesis and Biological Evaluation of their Antituberculosis Activity

Current Drug Discovery Technologies ◽

10.2174/1570163816666190411110331 ◽

2020 ◽

Vol 17 (3) ◽

pp. 365-375

Author(s):

Vasyl Kovalishyn ◽

Diana Hodyna ◽

Vitaliy O. Sinenko ◽

Volodymyr Blagodatny ◽

Ivan Semenyuta ◽

...

Keyword(s):

Machine Learning ◽

Isonicotinic Acid ◽

Acid Hydrazide ◽

Predictive Ability ◽

Antitubercular Activity ◽

Biological Evaluation ◽

Starting Point ◽

Binary Classifiers ◽

Synthesis And Biological Evaluation

Background: Tuberculosis (TB) is an infection disease caused by Mycobacterium tuberculosis (Mtb) bacteria. One of the main causes of mortality from TB is the problem of Mtb resistance to known drugs. Objective: The goal of this work is to identify potent small molecule anti-TB agents by machine learning, synthesis and biological evaluation. Methods: The On-line Chemical Database and Modeling Environment (OCHEM) was used to build predictive machine learning models. Seven compounds were synthesized and tested in vitro for their antitubercular activity against H37Rv and resistant Mtb strains. Results: A set of predictive models was built with OCHEM based on a set of previously synthesized isoniazid (INH) derivatives containing a thiazole core and tested against Mtb. The predictive ability of the models was tested by a 5-fold cross-validation, and resulted in balanced accuracies (BA) of 61–78% for the binary classifiers. Test set validation showed that the models could be instrumental in predicting anti- TB activity with a reasonable accuracy (with BA = 67–79 %) within the applicability domain. Seven designed compounds were synthesized and demonstrated activity against both the H37Rv and multidrugresistant (MDR) Mtb strains resistant to rifampicin and isoniazid. According to the acute toxicity evaluation in Daphnia magna neonates, six compounds were classified as moderately toxic (LD50 in the range of 10−100 mg/L) and one as practically harmless (LD50 in the range of 100−1000 mg/L). Conclusion: The newly identified compounds may represent a starting point for further development of therapies against Mtb. The developed models are available online at OCHEM http://ochem.eu/article/11 1066 and can be used to virtually screen for potential compounds with anti-TB activity.

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