Drug-Repositioning Approach for the Discovery of Anti-Influenza Virus Activity of Japanese Herbal (Kampo) Medicines In Vitro: Potent High Activity of Daio-Kanzo-To.
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ABSTRACT:
SUBMITTER: Watanabe K
PROVIDER: S-EPMC6280228 | biostudies-other | 2018
REPOSITORIES: biostudies-other
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Project description:Medicinal plants and their secondary metabolites are progressively used in the treatment of diseases as a complementary medicine. Inflammation is a pathologic condition that includes a wide range of diseases such as rheumatic and immune-mediated conditions, diabetes, cardiovascular accident, and etcetera. We introduce some herbs which their anti-inflammatory effects have been evaluated in clinical and experimental studies. Curcuma longa, Zingiber officinale, Rosmarinus officinalis, Borago officinalis, evening primrose, and Devil's claw are some of the introduced medicinal herbs in this review. Since the treatment of inflammation is not a one-dimensional remedy, this review tries to reach a multidimensional therapeutic approach to inflammation with the help of herbal medicine and modification in lifestyle.
| S-EPMC4877453 | biostudies-other
Project description:BackgroundRepositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. The compound libraries of GlaxoSmithKline (GSK), Pfizer and AstraZeneca (AZ) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of US Food and Drug Administration (FDA)-approved drugs and other bio-actives were tested against Plasmodium falciparum blood stages.MethodsMolecules were tested initially against erythrocytic co-cultures of P. falciparum to measure proliferation inhibition using one of the following methods: SYBR®I dye DNA staining assay (3D7, K1 or NF54 strains); [(3)H] hypoxanthine radioisotope incorporation assay (3D7 and 3D7A strain); or 4',6-diamidino-2-phenylindole (DAPI) DNA imaging assay (3D7 and Dd2 strains). After review of the available clinical pharmacokinetic and safety data, selected compounds with low ?M activity and a suitable clinical profile were tested in vivo either in a Plasmodium berghei four-day test or in the P. falciparum Pf3D7(0087/N9) huSCID 'humanized' mouse model.ResultsOf the compounds included in the GSK and Pfizer sets, 3.8% (9/238) had relevant in vitro anti-malarial activity while 6/100 compounds from the AZ candidate drug library were active. In comparison, around 0.6% (24/3,800) of the FDA-approved drugs and other bio-actives were active. After evaluation of available clinical data, four investigational drugs, active in vitro were tested in the P. falciparum humanized mouse model: UK-112,214 (PAF-H1 inhibitor), CEP-701 (protein kinase inhibitor), CEP-1347 (protein kinase inhibitor), and PSC-833 (p-glycoprotein inhibitor). Only UK-112,214 showed significant efficacy against P. falciparum in vivo, although at high doses (ED90 131.3 mg/kg [95% CI 112.3, 156.7]), and parasitaemia was still present 96 hours after treatment commencement. Of the six actives from the AZ library, two compounds (AZ-1 and AZ-3) were marginally efficacious in vivo in a P. berghei model.ConclusionsRepositioning of existing therapeutics in malaria is an attractive proposal. Compounds active in vitro at ?M concentrations were identified. However, therapeutic concentrations may not be effectively achieved in mice or humans because of poor bio-availability and/or safety concerns. Stringent safety requirements for anti-malarial drugs, given their widespread use in children, make this a challenging area in which to reposition therapy.
| S-EPMC4021201 | biostudies-literature
Project description:BackgroundDrug repositioning, also known as drug repurposing, defines new indications for existing drugs and can be used as an alternative to drug development. In recent years, the accumulation of large volumes of information related to drugs and diseases has led to the development of various computational approaches for drug repositioning. Although herbal medicines have had a great impact on current drug discovery, there are still a large number of herbal compounds that have no definite indications.ResultsIn the present study, we constructed a computational model to predict the unknown pharmacological effects of herbal compounds using machine learning techniques. Based on the assumption that similar diseases can be treated with similar drugs, we used four categories of drug-drug similarity (e.g., chemical structure, side-effects, gene ontology, and targets) and three categories of disease-disease similarity (e.g., phenotypes, human phenotype ontology, and gene ontology). Then, associations between drug and disease were predicted using the employed similarity features. The prediction models were constructed using classification algorithms, including logistic regression, random forest and support vector machine algorithms. Upon cross-validation, the random forest approach showed the best performance (AUC = 0.948) and also performed well in an external validation assessment using an unseen independent dataset (AUC = 0.828). Finally, the constructed model was applied to predict potential indications for existing drugs and herbal compounds. As a result, new indications for 20 existing drugs and 31 herbal compounds were predicted and validated using clinical trial data.ConclusionsThe predicted results were validated manually confirming the performance and underlying mechanisms - for example, irinotecan as a treatment for neuroblastoma. From the prediction, herbal compounds were considered to be drug candidates for related diseases which is important to be further developed. The proposed prediction model can contribute to drug discovery by suggesting drug candidates from herbal compounds which have potentials but few were studied.
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Project description:Bai Shao (BS, the root of Paeonia lactiflora Pall.), a common Chinese herb in many recipes used to treat viral infection and liver diseases, is recognized for its ability to nourish menstruation, its Yin convergence, and as an antiperspirant. However, the mechanism and components for its antiviral function remain to be elucidated. In this study, an ethanolic extract of BS was further partitioned into aqueous and organic parts (EAex) for in vitro functional study and in vivo efficacy testing. EAex exhibited an IC50 of 0.016 ± 0.005 mg/mL against influenza virus A/WSN/33 (H1N1), with broad-spectrum inhibitory activity against different strains of human influenza A viruses, including clinical oseltamivir-resistant isolates and an H1N1pdm strain. The synthesis of both viral RNA and protein was profoundly inhibited when the cells were treated with EAex. A time-of-addition assay demonstrated that EAex exerted its antiviral activity at various stages of the virus replication cycle. We addressed its antiviral activity at virus entry and demonstrated that EAex inhibits viral hemagglutination and viral binding to and penetration into host cells. In vivo animal testing showed that 200 mg/kg/d of EAex offered significant protection against viral infection. We conclude that BS possesses antiviral activity and has the potential for development as an anti-influenza agent.
| S-EPMC4014724 | biostudies-literature
Project description:Sepsis is a systemic inflammatory syndrome (SIRS) caused by acute microbial infection, and it has an extremely high mortality rate. Tumor necrosis factor-α (TNF-α)-induced necroptosis contributes to the pathophysiology of sepsis, so inhibiting necroptosis might be expected to improve clinical outcomes in septic patients. Here we predicted candidate drugs for treating sepsis in silico by combining genes differentially expressed in septic patients and controls combined with interrogation of the Library of Integrated Network-based Cellular Signatures (LINCS) L1000 perturbation database. Sixteen candidate drugs were screened out through bioinformatics analysis, and the top candidate linifanib was validated in cellular and mouse models of TNF-α-induced necroptosis. Cell viability was measured using a luminescent ATP assay, while the effects of linifanib on necroptosis were investigated by western blotting, immunoprecipitation, and RIPK1 kinase assays. Linifanib effectively protected cells from necroptosis and rescued SIRS mice from TNF-α-induced shock and death. In vitro, linifanib directly suppressed RIPK1 kinase activity. In vivo, linifanib effectively reduced overexpressed IL-6, a marker of sepsis severity, in the lungs of SIRS mice. Our preclinical evidence using an integrated in silico and experimental drug repositioning approach supports the potential clinical utility of linifanib in septic patients. Further clinical validation is now warranted.
| S-EPMC9913023 | biostudies-literature
Project description:BackgroundInfluenza viruses are a major cause of morbidity and mortality around the world. More recently, a swine-origin influenza A (H1N1) virus that is spreading via human-to-human transmission has become a serious public concern. Although vaccination is the primary strategy for preventing infections, influenza antiviral drugs play an important role in a comprehensive approach to controlling illness and transmission. In addition, a search for influenza-inhibiting drugs is particularly important in the face of high rate of emergence of influenza strains resistant to several existing influenza antivirals.MethodsWe searched for novel anti-influenza inhibitors using a cell-based neutralization (inhibition of virus-induced cytopathic effect) assay. After screening 20,800 randomly selected compounds from a library from ChemDiv, Inc., we found that BPR1P0034 has sub-micromolar antiviral activity. The compound was resynthesized in five steps by conventional chemical techniques. Lead optimization and a structure-activity analysis were used to improve potency. Time-of-addition assay was performed to target an event in the virus life cycle.ResultsThe 50% effective inhibitory concentration (IC50) of BPR1P0034 was 0.42 +/- 0.11 microM, when measured with a plaque reduction assay. Viral protein and RNA synthesis of A/WSN/33 (H1N1) was inhibited by BPR1P0034 and the virus-induced cytopathic effects were thus significantly reduced. BPR1P0034 exhibited broad inhibition spectrum for influenza viruses but showed no antiviral effect for enteroviruses and echovirus 9. In a time-of-addition assay, in which the compound was added at different stages along the viral replication cycle (such as at adsorption or after adsorption), its antiviral activity was more efficient in cells treated with the test compound between 0 and 2 h, right after viral infection, implying that an early step of viral replication might be the target of the compound. These results suggest that BPR1P0034 targets the virus during viral uncoating or viral RNA importation into the nucleus.ConclusionsTo the best of our knowledge, BPR1P0034 is the first pyrazole-based anti-influenza compound ever identified and characterized from high throughput screening to show potent (sub-microM) antiviral activity. We conclude that BPR1P0034 has potential antiviral activity, which offers an opportunity for the development of a new anti-influenza virus agent.
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Project description:To identify a CCR5 antagonist as an HIV-1 entry inhibitor, we designed a novel series of indane derivatives based on conformational considerations. Modification on the indane ring led to the discovery of compound 22a (INCB9471) that exhibited high affinity for CCR5, potent anti-HIV-1 activity, high receptor selectivity, excellent oral bioavailability, and a tolerated safety profile. INCB9471 has entered human clinical trials.
| S-EPMC4007949 | biostudies-literature
Project description:In this study, 12 known cycloartane triterpenoids (1-12) with four different skeletons isolated from the roots of Souliea vaginata were screened for the first time for in vitro anti-HIV activity using AZT as a standard. Among the compounds, beesioside I (1) showed the highest potency against HIV-1NL4-3 with an EC50 value of 2.32 μM (CC50 > 40 μM). Preliminary structure-activity relationship (SAR) studies on 1 indicated that simple modification of its aglycone (13) could significantly influence the antiviral activity. Particularly, the introduction of an acyl group at the C-3 position of 13 led to significant improvement in both anti-HIV potency and selectivity index. Among all synthetically modified derivatives, compound 13g was the most potent compound with an EC50 value of 0.025 μM and TI value greater than 800, comparable to those of 3-O-(3',3'-dimethylsuccinyl)-betulinic acid (DSB, bevirimat). Other analogues exhibited strong to weak inhibition of HIV-1 replication in MT-4 cells. The length, carboxylic terminus, and C-3' dimethyl substitution of the C-3 side chain substantially affected the anti-HIV activity. Finally, compound 13g was an effective agent against HIV with high potential for further investigation.
| S-EPMC6464118 | biostudies-literature
Project description:Epilepsy is a central neurological disorder affecting individuals of all ages and causing unpredictable seizures. In spite of the improved efficacy of new antiepileptic drugs and novel therapy, there are still approximately 20%~30% of patients, who have either intractable or uncontrolled seizures. The epilepsy drug-target network (EDT) is constructed and successfully demonstrates the characteristics and efficacy of popularly used AEDs through the identification of causative genes for 60 epilepsy patients. We discovered that the causative genes of most intractable patients were not the targets of existing AEDs, as well as being very far from the etiological mechanisms of existing AEDs in the functional networks. We show that the existence of new drugs that target the causative genes of intractable epilepsy patients, which will be potential candidates for refractory epilepsy patients. Our systematic approach demonstrates a new possibility for drug repositioning through the combination of the drug-target and functional networks.
| S-EPMC6963462 | biostudies-literature
Project description:BackgroundJapanese Kampo medicine is a traditional medicine with roots in ancient Chinese medicine. Because traditional physicians had been abolished in Japan, the present mainstream of Kampo treatment is that physicians who learned modern Western medicine prescribe Kampo extract products based on Western medical diagnosis. This situation is different from that in other east Asian countries, and the physicians require scientific clinical evidence.MethodsClinical studies were searched from literature databases, clinical trial registry sites, and "Evidence Reports of Kampo Treatment (EKAT)" published by the Japan Society for Oriental Medicine.ResultsAt the approval of Kampo products, scientific clinical evidence was not required because they have a long-period experience as a decoction. However, in the 1990s, Kampo products became a subject for national reevaluation; double-blind and placebo-controlled clinical trials. At the time, a methodological foundation for conducting clinical assessments of Kampo medicines was established. From 2000 onwards, with the evidence-based medicine era, the field of Kampo medicine also saw many randomized controlled trials, and their evidence was collected and published as EKAT. In the 2010s, post-marketing clinical trials of Kampo products also had to be conducted in this environment due to the need for ethical and scientific assurance. Currently, there are numerous clinical trials of Kampo products being conducted with high-grade trial designs.ConclusionThe situation of Kampo clinical studies reflects the unique history and position of Kampo medical system and Kampo products in Japan.
| S-EPMC8181179 | biostudies-literature