High-Content Screening for Cryptosporidium Drug Discovery

2019 ◽  
pp. 303-317 ◽  
Author(s):  
Melissa S. Love ◽  
Case W. McNamara
Keyword(s):  
Drug Discovery ◽  
High Content Screening

Development of a High-Content Screening Assay Panel to Accelerate Mechanism of Action Studies for Oncology Research

2012 ◽  
Vol 17 (8) ◽  
pp. 1005-1017 ◽  
Author(s):  
Danli L. Towne ◽  
Emily E. Nicholl ◽  
Kenneth M. Comess ◽  
Scott C. Galasinski ◽  
Philip J. Hajduk ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Mechanism Of Action ◽  
Large Scale ◽  
Morphological Changes ◽  
Single Cells ◽  
High Content Screening ◽  
Individual Compound ◽  
Screening Assay ◽  
Oncology Research ◽  
Protein Functions

Efficient elucidation of the biological mechanism of action of novel compounds remains a major bottleneck in the drug discovery process. To address this need in the area of oncology, we report the development of a multiparametric high-content screening assay panel at the level of single cells to dramatically accelerate understanding the mechanism of action of cell growth–inhibiting compounds on a large scale. Our approach is based on measuring 10 established end points associated with mitochondrial apoptosis, cell cycle disruption, DNA damage, and cellular morphological changes in the same experiment, across three multiparametric assays. The data from all of the measurements taken together are expected to help increase our current understanding of target protein functions, constrain the list of possible targets for compounds identified using phenotypic screens, and identify off-target effects. We have also developed novel data visualization and phenotypic classification approaches for detailed interpretation of individual compound effects and navigation of large collections of multiparametric cellular responses. We expect this general approach to be valuable for drug discovery across multiple therapeutic areas.

A novel multi-parametric high content screening assay in ciPTEC-OAT1 to predict drug-induced nephrotoxicity during drug discovery

2018 ◽  
Vol 92 (10) ◽  
pp. 3175-3190 ◽  
Author(s):  
Anna-Karin Sjögren ◽  
Katarina Breitholtz ◽  
Ernst Ahlberg ◽  
Lucas Milton ◽  
Malin Forsgard ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Content Screening ◽  
Screening Assay ◽  
Drug Induced

scholarly journals High content screening for drug discovery from traditional Chinese medicine

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Jing Wang ◽  
Ming-Yue Wu ◽  
Jie-Qiong Tan ◽  
Min Li ◽  
Jia-Hong Lu
Keyword(s):  
Drug Discovery ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
High Content Screening

High-Content Screening with siRNA Optimizes a Cell Biological Approach to Drug Discovery: Defining the Role of P53 Activation in the Cellular Response to Anticancer Drugs

2004 ◽  
Vol 9 (7) ◽  
pp. 557-568 ◽  
Author(s):  
Kenneth A. Giuliano ◽  
Yih-Tai Chen ◽  
D. Lansing Taylor
Keyword(s):  
Cell Cycle ◽  
Drug Discovery ◽  
Anticancer Drugs ◽  
Cellular Response ◽  
P53 Protein ◽  
High Content Screening ◽  
M Cell ◽  
Model Application ◽  
Rnai Technology ◽  
Blocking Activity

Deciphering the effects of compounds on molecular events within living cells is becoming an increasingly important component of drug discovery. In a model application of the industrial drug discovery process, the authors profiled a panel of 22 compounds using hierarchical cluster analysis of multiparameter high-content screening measurements from nearly 500,000 cells per microplate. RNAi protein knockdown methodology was used with high-content screening to dissect the effects of 2 anticancer drugs on multiple target activities. Camptothecin activated p53 in A549 lung carcinoma cells pretreated with scrambled siRNA, exhibited concentration-dependent cell cycle blocks, and induced moderate microtubule stabilization. Knockdown of camptothecin-induced p53 protein expression with p53 siRNA inhibited the G1/S blocking activity of the drug and diminished its microtubule-stabilizing activity. Paclitaxel activated p53 protein at low concentrations but exhibited G2/M cell cycle blocking activity at higher concentrations where microtubules were stabilized. In cells treated with p53 siRNA, paclitaxel failed to activate p53 protein, but the knockdown did not have a significant effect on the ability of paclitaxel to stabilize microtubules or induce a G2/M cell cycle block. Thus, this model application of the use of RNAi technology within the context of high-content screening shows the potential to provide massive amounts of combinatorial cell biological information on the temporal and spatial responses that cells mount to treatment by promising therapeutic candidates.

scholarly journals A Novel High-Content Screening-Based Method for Anti-Trypanosoma cruzi Drug Discovery Using Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Diogo Crispim Nascimento Portella ◽  
Erik Aranha Rossi ◽  
Bruno Diaz Paredes ◽  
Tanira Matutino Bastos ◽  
Cássio Santana Meira ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Imaging System ◽  
Rapid Assessment ◽  
Chronic Phase ◽  
Induced Pluripotent Stem Cell ◽  
High Content Screening ◽  
Reference Drug ◽  
Induced Pluripotent

Chagas disease is caused by Trypanosoma cruzi infection and remains a relevant cause of chronic heart failure in Latin America. The pharmacological arsenal for Chagas disease is limited, and the available anti-T. cruzi drugs are not effective when administered during the chronic phase. Cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) have the potential to accelerate the process of drug discovery for Chagas disease, through predictive preclinical assays in target human cells. Here, we aimed to establish a novel high-content screening- (HCS-) based method using hiPSC-CMs to simultaneously evaluate anti-T. cruzi activity and cardiotoxicity of chemical compounds. To provide proof-of-concept data, the reference drug benznidazole and three compounds with known anti-T. cruzi activity (a betulinic acid derivative named BA5 and two thiazolidinone compounds named GT5A and GT5B) were evaluated in the assay. hiPSC-CMs were infected with T. cruzi and incubated for 48 h with serial dilutions of the compounds for determination of EC50 and CC50 values. Automated multiparametric analyses were performed using an automated high-content imaging system. Sublethal toxicity measurements were evaluated through morphological measurements related to the integrity of the cytoskeleton by phalloidin staining, nuclear score by Hoechst 33342 staining, mitochondria score following MitoTracker staining, and quantification of NT-pro-BNP, a peptide released upon mechanical myocardial stress. The compounds showed EC50 values for anti-T. cruzi activity similar to those previously described for other cell types, and GT5B showed a pronounced trypanocidal activity in hiPSC-CMs. Sublethal changes in cytoskeletal and nucleus scores correlated with NT-pro-BNP levels in the culture supernatant. Mitochondrial score changes were associated with increased cytotoxicity. The assay was feasible and allowed rapid assessment of anti-T. cruzi action of the compounds, in addition to cardiotoxicity parameters. The utilization of hiPSC-CMs in the drug development workflow for Chagas disease may help in the identification of novel compounds.

Image-based high-content screening in drug discovery

2020 ◽  
Vol 25 (8) ◽  
pp. 1348-1361 ◽  
Author(s):  
Sean Lin ◽  
Kenji Schorpp ◽  
Ina Rothenaigner ◽  
Kamyar Hadian
Keyword(s):  
Drug Discovery ◽  
High Content Screening

Bioorthogonal Probes for the Study of MDM2-p53 Inhibitors in Cells and Development of High-Content Screening Assays for Drug Discovery

2016 ◽  
Vol 55 (52) ◽  
pp. 16026-16030 ◽  
Author(s):  
Pier Luca D'Alessandro ◽  
Nicole Buschmann ◽  
Markus Kaufmann ◽  
Pascal Furet ◽  
Frederic Baysang ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Content Screening ◽  
Screening Assays ◽  
In Cells

scholarly journals Shortening the drug discovery pipeline: small molecule high content screening for lead discovery in neglected disease

2011 ◽  
Vol 5 (S1) ◽  
Author(s):  
Jonathan Cechetto ◽  
Hee Kyoung Jeon ◽  
Jiyeon Jang ◽  
Doyoon Kwon ◽  
Thierry Christophe ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
High Content Screening ◽  
Lead Discovery ◽  
Neglected Disease ◽  
Discovery Pipeline
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