scholarly journals High-throughput behavioral screen in C. elegans reveals novel Parkinson’s disease drug candidates

2020 ◽  
Author(s):  
Salman Sohrabi ◽  
Danielle E. Mor ◽  
Rachel Kaletsky ◽  
William Keyes ◽  
Coleen T. Murphy
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
High Throughput ◽  
C Elegans ◽  
Drug Candidates ◽  
Branched Chain Amino Acid ◽  
Branched Chain ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Behavioral Screen

AbstractWe recently linked branched-chain amino acid transferase 1 (BCAT1) with the movement disorder Parkinson’s disease (PD), and found that reduction of C. elegans bcat-1 causes abnormal spasm-like ‘curling’ behavior with age. Here, we report the development of a high-throughput automated curling assay and its application to the discovery of new potential PD therapeutics. Four FDA-approved drugs were identified as candidates for late-in-life intervention, with metformin showing the greatest promise for repurposing to PD.

scholarly journals High-throughput behavioral screen in C. elegans reveals Parkinson’s disease drug candidates

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Salman Sohrabi ◽  
Danielle E. Mor ◽  
Rachel Kaletsky ◽  
William Keyes ◽  
Coleen T. Murphy
Keyword(s):  
Neural Network ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
High Throughput ◽  
Potential Candidate ◽  
Automated Scoring ◽  
C Elegans ◽  
Drug Candidates ◽  
Branched Chain ◽  
Approved Drugs

AbstractWe recently linked branched-chain amino acid transferase 1 (BCAT1) dysfunction with the movement disorder Parkinson’s disease (PD), and found that RNAi-mediated knockdown of neuronal bcat-1 in C. elegans causes abnormal spasm-like ‘curling’ behavior with age. Here we report the development of a machine learning-based workflow and its application to the discovery of potentially new therapeutics for PD. In addition to simplifying quantification and maintaining a low data overhead, our simple segment-train-quantify platform enables fully automated scoring of image stills upon training of a convolutional neural network. We have trained a highly reliable neural network for the detection and classification of worm postures in order to carry out high-throughput curling analysis without the need for user intervention or post-inspection. In a proof-of-concept screen of 50 FDA-approved drugs, enasidenib, ethosuximide, metformin, and nitisinone were identified as candidates for potential late-in-life intervention in PD. These findings point to the utility of our high-throughput platform for automated scoring of worm postures and in particular, the discovery of potential candidate treatments for PD.

scholarly journals Integrated network analysis identifying potential novel drug candidates and targets for Parkinson's disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Pusheng Quan ◽  
Kai Wang ◽  
Shi Yan ◽  
Shirong Wen ◽  
Chengqun Wei ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Target ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Control Group ◽  
Drug Candidates ◽  
Novel Drug

AbstractThis study aimed to identify potential novel drug candidates and targets for Parkinson’s disease. First, 970 genes that have been reported to be related to PD were collected from five databases, and functional enrichment analysis of these genes was conducted to investigate their potential mechanisms. Then, we collected drugs and related targets from DrugBank, narrowed the list by proximity scores and Inverted Gene Set Enrichment analysis of drug targets, and identified potential drug candidates for PD treatment. Finally, we compared the expression distribution of the candidate drug-target genes between the PD group and the control group in the public dataset with the largest sample size (GSE99039) in Gene Expression Omnibus. Ten drugs with an FDR < 0.1 and their corresponding targets were identified. Some target genes of the ten drugs significantly overlapped with PD-related genes or already known therapeutic targets for PD. Nine differentially expressed drug-target genes with p < 0.05 were screened. This work will facilitate further research into the possible efficacy of new drugs for PD and will provide valuable clues for drug design.

scholarly journals Endoplasmic Reticulum Stress Regulators: New Drug Targets for Parkinson’s Disease

2021 ◽  
pp. 1-10
Author(s):  
Vera Kovaleva ◽  
Mart Saarma
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Er Stress ◽  
Protein Misfolding ◽  
Drug Targets ◽  
Dopamine Neurons ◽  
Drug Candidates ◽  
The Unfolded Protein Response

Parkinson’s disease (PD) pathology involves progressive degeneration and death of vulnerable dopamine neurons in the substantia nigra. Extensive axonal arborisation and distinct functions make this type of neurons particularly sensitive to homeostatic perturbations, such as protein misfolding and Ca2 + dysregulation. Endoplasmic reticulum (ER) is a cell compartment orchestrating protein synthesis and folding, as well as synthesis of lipids and maintenance of Ca2 +-homeostasis in eukaryotic cells. When misfolded proteins start to accumulate in ER lumen the unfolded protein response (UPR) is activated. UPR is an adaptive signalling machinery aimed at relieving of protein folding load in the ER. When UPR is chronic, it can either boost neurodegeneration and apoptosis or cause neuronal dysfunctions. We have recently discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) exerts its prosurvival action in dopamine neurons and in animal model of PD through the direct binding to UPR sensor inositol-requiring protein 1 alpha (IRE1α) and attenuation of UPR. In line with this, UPR targeting resulted in neuroprotection and neurorestoration in various preclinical PD animal models. Therefore, growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics. In this review, we discuss ER stress as a therapeutic target to treat PD; we summarize the existing preclinical data on the regulation of ER stress for PD treatment. In addition, we point out the crucial aspects for successful clinical translation of UPR-regulating GFs and new prospective in GFs-based treatments of PD, focusing on ER stress regulation.

Potential role of protein stabilizers in amelioration of Parkinson's disease and associated effects in transgenic Caenorhabditis elegans model expressing alpha-synuclein

RSC Advances ◽  
2015 ◽  
Vol 5 (95) ◽  
pp. 77706-77715 ◽  
Author(s):  
Supinder Kaur ◽  
Aamir Nazir
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Caenorhabditis Elegans ◽  
Potential Role ◽  
Alpha Synuclein ◽  
C Elegans

Studies employing transgenicC. elegansmodel show that trehalose, a protein stabilizer, alleviates manifestations associated with Parkinson's diseaseviaits inherent activity and through induction of autophagic machinery.

scholarly journals PS4DR: A multimodal workflow for identification and prioritization of drugs based on pathway signatures

2020 ◽  
Author(s):  
Mhammad Asif Emon ◽  
Daniel Domingo-Fernández ◽  
Charles Tapley Hoyt ◽  
Martin Hofmann-Apitius
Keyword(s):  
Gene Expression ◽  
Genome Wide Association Study ◽  
Drug Repositioning ◽  
Heterogeneous Data ◽  
New Drugs ◽  
Gwas Data ◽  
Drug Candidates ◽  
Gene Expression Signatures ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract Background: During the last decade, there has been a surge towards computational drug repositioning owing to constantly increasing -omics data in the biomedical research field. While numerous existing methods focus on the integration of heterogeneous data to propose candidate drugs, it is still challenging to substantiate their results with mechanistic insights of these candidate drugs. Therefore, there is a need for more innovative and efficient methods which can enable better integration of data and knowledge for drug repositioning. Results: Here, we present a customizable workflow ( PS4DR) which not only integrates high-throughput data such as genome-wide association study (GWAS) data and gene expression signatures from disease and drug perturbations but also takes pathway knowledge into consideration to predict drug candidates for repositioning. We have collected and integrated publicly available GWAS data and gene expression signatures for several diseases and hundreds of FDA-approved drugs or those under clinical trial in this study. Additionally, different pathway databases were used for mechanistic knowledge integration in the workflow. Using this systematic consolidation of data and knowledge, the workflow computes pathway signatures that assist in the prediction of new indications for approved and investigational drugs. Conclusion: We showcase PS4DR with applications demonstrating how this tool can be used for repositioning and identifying new drugs as well as proposing drugs that can simulate disease dysregulations. We were able to validate our workflow by demonstrating its capability to predict FDA-approved drugs for their known indications for several diseases. Further, PS4DR returned many potential drug candidates for repositioning that were backed up by epidemiological evidence extracted from scientific literature. Source code is freely available at https://github.com/ps4dr/ps4dr .

scholarly journals Screening of FDA Approved Drugs Against COVID-19 Main Protease: Coronavirus Disease

2020 ◽  
Author(s):  
Vijayakumar Balakrishnan ◽  
Karthik Lakshminarayanan
Keyword(s):  
Vaccine Development ◽  
New Drugs ◽  
World Health ◽  
Wuhan City ◽  
Drug Candidates ◽  
Human Contact ◽  
Main Protease ◽  
Potent Drug ◽  
Approved Drugs ◽  
Fda Approved Drugs

In the end of December 2019, a new strain of coronavirus was identified in the Wuhan city of Hubei province in China. Within a shorter period of time, an unprecedented outbreak of this strain was witnessed over the entire Wuhan city. This novel coronavirus strain was later officially renamed as COVID-19 (Coronavirus disease 2019) by the World Health Organization. The mode of transmission had been found to be human-to-human contact and hence resulted in a rapid surge across the globe where more than 1,100,000 people have been infected with COVID-19. In the current scenario, finding potent drug candidates for the treatment of COVID-19 has emerged as the most challenging task for clinicians and researchers worldwide. Identification of new drugs and vaccine development may take from a few months to years based on the clinical trial processes. To overcome the several limitations involved in identifying and bringing out potent drug candidates for treating COVID-19, in the present study attempts were made to screen the FDA approved drugs using High Throughput Virtual Screening (HTVS). The COVID-19 main protease (COVID-19 Mpro) was chosen as the drug target for which the FDA approved drugs were initially screened with HTVS. The drug candidates that exhibited favorable docking score, energy and emodel calculations were further taken for performing Induced Fit Docking (IFD) using Schrodinger&rsquo;s GLIDE. From the flexible docking results, the following four FDA approved drugs Sincalide, Pentagastrin, Ritonavir and Phytonadione were identified. In particular, Sincalide and Pentagastrin can be considered potential key players for the treatment of COVID-19 disease.

CRISPR System: A High-throughput Toolbox for Research and Treatment of Parkinson’s Disease

2019 ◽  
Vol 40 (4) ◽  
pp. 477-493 ◽  
Author(s):  
Fatemeh Safari ◽  
Gholamreza Hatam ◽  
Abbas Behzad Behbahani ◽  
Vahid Rezaei ◽  
Mazyar Barekati‑Mowahed ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
High Throughput ◽  
Crispr System ◽  
System A

scholarly journals Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections

2018 ◽  
Vol 115 (41) ◽  
pp. E9649-E9658 ◽  
Author(s):  
Mario D. Garcia ◽  
Sheena M. H. Chua ◽  
Yu-Shang Low ◽  
Yu-Ting Lee ◽  
Kylie Agnew-Francis ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antifungal Drug ◽  
New Drugs ◽  
Acetohydroxyacid Synthase ◽  
Drug Candidates ◽  
New Class ◽  
Branched Chain Amino Acid ◽  
Low Toxicity ◽  
Chlorimuron Ethyl ◽  
Branched Chain

The increased prevalence of drug-resistant human pathogenic fungal diseases poses a major threat to global human health. Thus, new drugs are urgently required to combat these infections. Here, we demonstrate that acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway, is a promising new target for antifungal drug discovery. First, we show that several AHAS inhibitors developed as commercial herbicides are powerful accumulative inhibitors of Candida albicans AHAS (Ki values as low as 800 pM) and have determined high-resolution crystal structures of this enzyme in complex with several of these herbicides. In addition, we have demonstrated that chlorimuron ethyl (CE), a member of the sulfonylurea herbicide family, has potent antifungal activity against five different Candida species and Cryptococcus neoformans (with minimum inhibitory concentration, 50% values as low as 7 nM). Furthermore, in these assays, we have shown CE and itraconazole (a P450 inhibitor) can act synergistically to further improve potency. Finally, we show in Candida albicans-infected mice that CE is highly effective in clearing pathogenic fungal burden in the lungs, liver, and spleen, thus reducing overall mortality rates. Therefore, in view of their low toxicity to human cells, AHAS inhibitors represent a new class of antifungal drug candidates.

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