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Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1196
Author(s):  
Y. Q. Shirleen Soh ◽  
Keara D. Malone ◽  
Rachel T. Eguia ◽  
Jesse D. Bloom

Antivirals are used not only in the current treatment of influenza but are also stockpiled as a first line of defense against novel influenza strains for which vaccines have yet to be developed. Identifying drug resistance mutations can guide the clinical deployment of the antiviral and can additionally define the mechanisms of drug action and drug resistance. Pimodivir is a first-in-class inhibitor of the polymerase basic protein 2 (PB2) subunit of the influenza A virus polymerase complex. A number of resistance mutations have previously been identified in treated patients or cell culture. Here, we generate a complete map of the effect of all single-amino-acid mutations to an avian PB2 on resistance to pimodivir. We identified both known and novel resistance mutations not only in the previously implicated cap-binding and mid-link domains, but also in the N-terminal domain. Our complete map of pimodivir resistance thus enables the evaluation of whether new viral strains contain mutations that will confer pimodivir resistance.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ryuichi Sakate ◽  
Tomonori Kimura

AbstractDrug development for rare and intractable diseases has been challenging for decades due to the low prevalence and insufficient information on these diseases. Drug repositioning is increasingly being used as a promising option in drug development. We aimed to analyze the trend of drug repositioning and inter-disease drug repositionability among rare and intractable diseases. We created a list of rare and intractable diseases based on the designated diseases in Japan. Drug information extracted from clinical trial data were integrated with information of drug target genes, which represent the mechanism of drug action. We obtained 753 drugs and 551 drug target genes from 8307 clinical trials for 189 diseases or disease groups. Trend analysis of drug sharing between a disease pair revealed that 1676 drug repositioning events occurred in 4401 disease pairs. A score, Rgene, was invented to investigate the proportion of drug target genes shared between a disease pair. Annual changes of Rgene corresponded to the trend of drug repositioning and predicted drug repositioning events occurring within a year or two. Drug target gene-based analyses well visualized the drug repositioning landscape. This approach facilitates drug development for rare and intractable diseases.


Nano LIFE ◽  
2021 ◽  
Vol 11 (02) ◽  
pp. 2130004
Author(s):  
Amreen Khan ◽  
Nishant K. Jain ◽  
Mayuri Gandhi ◽  
Rajendra Prasad ◽  
Rohit Srivastava

Cancer is one of the most prevalent diseases with mortality rate considerably increasing every year. Conventional treatment strategies for cancer like chemotherapy suffer from the drawbacks of multiple-dose requirements and non-specificity of drug action. Moreover, the cost involved in the diagnosis and treatment is very high. Recently, the application of nanotechnology in the field of cancer has witnessed tremendous significance due to the unique size, shape, and surface properties of nanomaterials. With the intention to utilize biocompatible and biodegradable nanomaterials in cancer and reduce the non-specificity, approaches such as targeted nanotherapeutics came into existence. Besides having therapeutic potential, some materials demonstrate their applicability in bioimaging forecasting distinct optical properties. In this review, we have discussed the basics and principles guiding the design of different photo-triggered nanotheranostic materials used in cancer. Additionally, recent developments and advantages offered by the NIR-responsive photodynamic and photothermal agents along with their future scope have been presented. An overview of the toxicity and clinical prospect of photosensitive agents is also summarized. Overall, the field of photo-triggered cancer nanotheranostics has huge potential that can be clinically translated into an affordable and safe treatment approach.


2021 ◽  
Vol 14 (6) ◽  
pp. 526
Author(s):  
Sławomir Murawiec ◽  
Marek Krzystanek

Despite treating depression with antidepressants, their effectiveness is often insufficient. Comparative effectiveness studies and meta-analyses show the effectiveness of antidepressants; however, they do not provide clear indications as to the choice of a specific antidepressant. The rational choice of antidepressants may be based on matching their mechanisms of action to the symptomatic profiles of depression, reflecting the heterogeneity of symptoms in different patients. The authors presented a series of cases of patients diagnosed with depression in whom at least one previous antidepressant treatment was shown to be ineffective before drug targeted symptom cluster-matching treatment (SCMT). The presented pilot study shows for the first time the effectiveness of SCMT in the different clusters of depressive symptoms. All the described patients obtained recovery from depressive symptoms after introducing drug-targeted SCMT. Once validated in clinical trials, SCMT might become an effective and rational method of selecting an antidepressant according to the individual profile of depressive symptoms, the mechanism of their formation, and the mechanism of drug action. Although the study results are preliminary, SCMT can be a way to personalize treatment, increasing the likelihood of improvement even in patients who meet criteria for treatment-resistant depression.


Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2637
Author(s):  
Aleksandra Maciejczyk ◽  
Justyna Kapral-Piotrowska ◽  
Joanna Sumorek-Wiadro ◽  
Adrian Zając ◽  
Ewa Grela ◽  
...  

Aim: The anti-glioma effect of lensoside Aβ alone and in combination with sorafenib (pro-survival Raf kinase inhibitor) was evaluated for the first time in terms of programmed cell death induction in anaplastic astrocytoma and glioblastoma multiforme cell lines as an experimental model. Apoptosis, autophagy, and necrosis were identified microscopically (fluorescence and scanning microscopes) and confirmed by flow cytometry (mitochondrial membrane potential MMP and cell death). The expression of apoptotic (caspase 3) and autophagic markers (beclin 1) as well as Raf kinase were estimated by immunoblotting. The FTIR method was used to determine the interaction of the studied drugs with lipid and protein groups within cells, while the modes of drug action within the cells were assessed with the FLIM technique. Results: Lensoside Aβ itself does not exhibit anti-glioma activity but significantly enhances the anti-cancer potential of sorafenib, initiating mainly apoptosis of up to 90% of cells. It was correlated with an increased level of active caspase 3, a reduced MMP value, and a lower level of Raf kinase. The interaction with membrane structures led to morphological changes typical of programmed death. Conclusions: Our results indicate that lensoside Aβ plays an important role as an adjuvant in chemotherapy with sorafenib and may be a potential candidate in anti-glioma combination therapy.


2021 ◽  
Author(s):  
Adith S Arun ◽  
Sung-Cheol Kim ◽  
Mehmet Eren Ahsen ◽  
Gustavo A Stolovitzky

Identifying and characterizing the effect of combination cancer therapies is of paramount importance in cancer research. The benefit of a combination can either be due to inherent heterogeneity in patient populations or because of molecular synergy between the compounds given in combination, usually studied in cell culture, or both. To shed light and help characterized combinations and their enhanced benefits over single therapies, we introduce Correlated Drug Action (CDA) as a baseline additivity model. We formulate the CDA model as a closed-form expression, which lends itself to be scalable and interpretable, both in the temporal domain (tCDA) to explain survival curves, and in the dose domain (dCDA), to explain dose-response curves. CDA can be used in clinical trials and cell culture experiments. At the level of clinical trials, we demonstrate tCDA's utility in explaining the benefit of clinical combinations, identifying non-additive combinations, and cases where biomarkers may be able to decouple the combination into monotherapies. At the level of cells in culture, dCDA naturally embodies null models such as Bliss additivity and the Highest Single Agent model as special cases, and can be extended to be sham combination compliant. We demonstrate the applicability of dCDA in assessing non-additive combinations and doses. Additionally, we introduce a new synergy metric, Excess over CDA (EOCDA), that incorporates elements of Bliss additivity and dose equivalence concepts in the same measure. CDA is a novel general framework for additivity at the cell line and patient population levels and provides a method to characterize and quantify the action of drug combinations.


2021 ◽  
Vol 118 (20) ◽  
pp. e2025846118
Author(s):  
Shane C. Wright ◽  
Viktoriya Lukasheva ◽  
Christian Le Gouill ◽  
Hiroyuki Kobayashi ◽  
Billy Breton ◽  
...  

G protein–coupled receptors (GPCRs) are gatekeepers of cellular homeostasis and the targets of a large proportion of drugs. In addition to their signaling activity at the plasma membrane, it has been proposed that their actions may result from translocation and activation of G proteins at endomembranes—namely endosomes. This could have a significant impact on our understanding of how signals from GPCR-targeting drugs are propagated within the cell. However, little is known about the mechanisms that drive G protein movement and activation in subcellular compartments. Using bioluminescence resonance energy transfer (BRET)–based effector membrane translocation assays, we dissected the mechanisms underlying endosomal Gq trafficking and activity following activation of Gq-coupled receptors, including the angiotensin II type 1, bradykinin B2, oxytocin, thromboxane A2 alpha isoform, and muscarinic acetylcholine M3 receptors. Our data reveal that GPCR-promoted activation of Gq at the plasma membrane induces its translocation to endosomes independently of β-arrestin engagement and receptor endocytosis. In contrast, Gq activity at endosomes was found to rely on both receptor endocytosis-dependent and -independent mechanisms. In addition to shedding light on the molecular processes controlling subcellular Gq signaling, our study provides a set of tools that will be generally applicable to the study of G protein translocation and activation at endosomes and other subcellular organelles, as well as the contribution of signal propagation to drug action.


2021 ◽  
Author(s):  
Y.Q. Shirleen Soh ◽  
Keara D. Malone ◽  
Rachel T. Eguia ◽  
Jesse D Bloom

Antivirals are used not only in current treatment of influenza, but are also stockpiled as a first line of defense against novel influenza strains for which vaccines have yet to be developed. Identifying drug resistance mutations can guide clinical deployment of the antiviral, and additionally define the mechanisms of drug action and drug resistance. Pimodivir is a first-in-class inhibitor of the polymerase basic protein 2 (PB2) subunit of the influenza A virus polymerase complex. A number of resistance mutations have previously been identified in treated patients or cell culture. Here, we generate a complete map of the effect of all single-amino-acid mutations to an avian PB2 on resistance to pimodivir. We identified both known and novel resistance mutations not only in the previously implicated cap-binding and mid-link domains, but also in the N-terminal domain. Our complete map of pimodivir resistance thus enables the evaluation of whether new viral strains contain mutations that will confer pimodivir resistance.


2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yue Lu ◽  
Yao Qi ◽  
Li Li ◽  
Yuhong Yan ◽  
Danni Yao ◽  
...  

Background. This study aimed to explore the mechanisms of action of the PSORI-CM01 and Yinxieling formulas in the treatment of patients with psoriasis vulgaris by analyzing gene expression in peripheral blood mononuclear cells (PBMCs). Methods. PBMC samples were collected from 21 patients before and after treatment. The study included nine patients in the PSORI-CM01 treatment group, 12 patients in the Yinxieling treatment group, and nine patients in the healthy control group. Gene expression levels in PBMCs were determined using the Affymetrix gene chip technology. Results. In the PSORI-CM01 group before and after treatment, a total of 668 differentially expressed genes were found, of which 445 were upregulated and 223 were downregulated. Before and after Yinxieling treatment, 657 differentially expressed genes were found, of which 168 were upregulated and 489 were downregulated. Venn analysis showed that 78 genes were not differentially expressed in the PSORI-CM01 group and 74 were not differentially expressed in the Yinxieling group compared with those in the controls. Among these genes, 72 genes were common to both groups, which were the genes on which the two drugs acted jointly. The results of KEGG analysis and Venn analysis on the signalling pathways of drug action in treatment groups showed that haemostasis and pathways involving Rho GTPases were common signalling pathways of drug action in the two groups. Conclusions. By a comparative analysis of the treatment groups, we found that both drugs have a positive effect on patients with psoriasis vulgaris, primarily by regulating the pathways related to platelet activation, aggregation, and blood coagulation. Trial registration: ChiCTR, ChiCTR-TRC-14005185, Registered 8 August 2014, http://www.chictr.org.cn/showproj.aspx?proj=4390


2021 ◽  
Vol 2 (2) ◽  
pp. 074-086
Author(s):  
Harith M. Al-ajely

It is well known from FDA reports that More than 75% of the heterocyclic compounds are drugs and 90 of heterocyclic compounds are cancer drugs. The nitrogen-based heterocycles occupy an exclusive position as a valuable source of therapeutic agents in medicinal chemistry. Most drugs approved by the FDA and currently available in the market are nitrogen-containing heterocyclic moieties, More over heterocyclic compounds are important class of organic chemistry due to their widely spread in nature. Also there are many route for their action and many mechanistic pathways for their preparation and different metabolic actions. This comes from the easily building or removal of any functional group within the molecules. Changing just on group cause to change the metabolic pathway of the drug action and site of attack of the desired target accordingly. This great characteristic value make them much more important in drug discovery programs of many researchers and also encouraged us and drew attentions of other researchers to develop new ways for their synthesis. As a result different pharmacological and medical applications. Oxazie compounds are sub branch of heterocyclic compounds. These compounds having two hetero atoms, Oxygen and nitrogen within their structures make them much more important toward therapeutic studies. We are here in our investigation will focus on the methodologies and the therapeutic action of the titled compounds as well as other various applications.


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