scholarly journals A humanized phenotypic screening platform for chronic pain

2017 ◽  
Vol 14 (6) ◽  
pp. 636-636
Author(s):  
Daniel Tams ◽  
Paul Karila ◽  
Ashley Barnes
Keyword(s):  
Chronic Pain ◽  
Phenotypic Screening ◽  
Screening Platform

scholarly journals Compounds enhancing human sperm motility identified using a high-throughput phenotypic screening platform

2021 ◽  
Author(s):  
Franz S. Gruber ◽  
Zoe C. Johnston ◽  
Neil R. Norcross ◽  
Irene Georgiou ◽  
Caroline Wilson ◽  
...  
Keyword(s):  
Sperm Motility ◽  
High Throughput ◽  
Dose Response ◽  
High Throughput Screening ◽  
Human Sperm ◽  
Sperm Function ◽  
Phenotypic Screening ◽  
Enhancing Effect ◽  
Short Period ◽  
Screening Platform

AbstractStudy questionCan a high-throughput screening platform facilitate male fertility drug discovery?Summary answerA high-throughput screening platform identified a large number of compounds that enhanced sperm motility.What is known alreadySeveral efforts to find small molecules modulating sperm function have been performed but not using high-throughput technology.Study design, size, durationHealthy donor semen samples were used and samples were pooled (3-5 donors per pool). Primary screening was performed in singlicate; dose-response screening was performed in duplicate (independent donor pools).Participants/materials, setting, methodsSpermatozoa isolated from healthy donors were prepared by density gradient centrifugation and incubated in 384-well plates with compounds (6.25 uM) to identify those compounds with enhancing effects on motility. A total of ∼17,000 compounds from the following libraries: ReFRAME, Prestwick, Tocris, LOPAC, CLOUD and MMV Pathogen Box were screened. Dose response experiments of screening hits were performed to confirm the enhancing effect on sperm motility. Experiments were performed in a University setting.Main results and the role of chanceFrom our primary single concentration screening, 105 compounds elicited an enhancing effect on sperm motility compared to DMSO treated wells. Confirmed enhancing compounds were grouped based on their annotated targets/target classes. A major target class, phosphodiesterase inhibitors, were identified in particular PDE10A inhibitors as well as number of compounds not previously identified/known to enhance human sperm motility such as those related to GABA signaling.Limitations, reasons for cautionCompounds have been tested with prepared donor spermatozoa and only incubated for a short period of time. Therefore, the effect of compounds on whole semen or with longer incubation time may be different. All experiments were performed in vitro.Wider implications of the findingsThis phenotypic screening assay identified a large number of compounds that increased sperm motility. In addition to furthering our understanding of human sperm function, for example identifying new avenues for discovery, we highlight potential inhibitors as promising start-point for a medicinal chemistry programme for potential enhancement of male infertility. Moreover, with disclosure of the results of screening we present a substantial resource to inform further work in the fieldStudy funding/competing interest(s)This study was supported by the Bill and Melinda Gates Foundation and Scottish Funding Council and Scottish Universities Life Science Alliance.

scholarly journals High Content Phenotypic Profiling in Oesophageal Adenocarcinoma Identifies Selectively Active Pharmacological Classes of Drugs for Repurposing and Chemical Starting Points for Novel Drug Discovery

2020 ◽  
Author(s):  
Rebecca E Hughes ◽  
Richard J R Elliott ◽  
Alison F Munro ◽  
Ashraff Makda ◽  
J Robert O’Neill ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Cell Lines ◽  
Cancer Biology ◽  
Large Scale ◽  
Oesophageal Adenocarcinoma ◽  
Phenotypic Screening ◽  
Chemical Library ◽  
Drug Mechanism ◽  
Screening Platform ◽  
Selective Activity

AbstractOesophageal adenocarcinoma (OAC) is a highly heterogeneous disease, dominated by large-scale genomic rearrangements and copy number alterations. Such characteristics have hampered conventional target-directed drug discovery and personalized medicine strategies contributing to poor outcomes for patients diagnosed with OAC. We describe the development and application of a phenotypic-led OAC drug discovery platform incorporating image-based, high-content cell profiling and associated image-informatics tools to classify drug mechanism-of-action (MoA). We applied a high-content Cell Painting assay to profile the phenotypic response of 19,555 compounds across a panel of six OAC cell lines representing the genetic heterogeneity of disease, a pre-neoplastic Barrett’s oesophagus line and a non-transformed squamous oesophageal line. We built an automated phenotypic screening and high-content image analysis pipeline to identify compounds that selectively modified the phenotype of OAC cell lines. We further trained a machine-learning model to predict the MoA of OAC selective compounds using phenotypic fingerprints from a library of reference compounds.We identified a number of phenotypic clusters enriched with similar pharmacological classes e.g. Methotrexate and three other antimetabolites which are highly selective for OAC cell lines. We further identify a small number of hits from our diverse chemical library which show potent and selective activity for OAC cell lines and which do not cluster with the reference library of known MoA, indicating they may be selectively targeting novel oesophageal cancer biology. Our results demonstrate that our OAC phenotypic screening platform can identify existing pharmacological classes and novel compounds with selective activity for OAC cell phenotypes.

High-throughput stem cell-based phenotypic screening through microniches

2019 ◽  
Vol 7 (8) ◽  
pp. 3471-3479
Author(s):  
Laura Kolb ◽  
Simone Allazetta ◽  
Maria Karlsson ◽  
Mehmet Girgin ◽  
Wilfried Weber ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Stem Cell ◽  
Cell Fate ◽  
High Throughput ◽  
Cell Behavior ◽  
Phenotypic Screening ◽  
Stem Cell Fate ◽  
Screening Platform

Methods for screening combinations of signals for their effects on stem cell behavior are needed in the field of tissue engineering. We introduce a microgel-based screening platform for testing combinations of proteins on stem cell fate.

Abstract B030: Development and validation of a phenotypic screening platform for the identification of novel immuno-oncology targets

2016 ◽  
Author(s):  
Virginie Rabolli ◽  
Murielle Martini ◽  
Ariane Scoumanne ◽  
Marie-Claire Letellier ◽  
Stefano Crosignani ◽  
...  
Keyword(s):  
Phenotypic Screening ◽  
Screening Platform ◽  
Development And Validation

scholarly journals A phenotypic screening platform utilising human spermatozoa identifies new compounds with contraceptive activity

2019 ◽  
Author(s):  
Franz Gruber ◽  
Christopher L.R. Barratt ◽  
Paul D. Andrews
Keyword(s):  
Drug Discovery ◽  
Target Identification ◽  
Human Sperm ◽  
Phenotypic Screening ◽  
Major Barrier ◽  
Drug Candidates ◽  
Critical Gap ◽  
Comprehensive Collection ◽  
Screening Platform ◽  
Novel Drug

AbstractThere is an urgent need to develop new methods for male contraception, however a major barrier to drug discovery has been the lack of validated targets and the absence of an effective high-throughput phenotypic screening system. To address this deficit, we developed a fully-automated robotic screening platform that provided quantitative evaluation of compound activity against two key attributes of human sperm function: motility and acrosome reaction. In order to accelerate contraceptive development, we screened the comprehensive collection of 12,000 molecules that make up the ReFRAME repurposing library, comprising nearly all the small molecules that have been approved or have undergone clinical development, or have significant preclinical profiling. We identified several compounds that potently inhibit motility representing either novel drug candidates or routes to target identification. This platform will now allow for major drug discovery programmes that address the critical gap in the contraceptive portfolio as well as uncover novel human sperm biology.

scholarly journals A phenotypic screening platform to identify small molecule modulators of Chlamydomonas reinhardtii growth, motility and photosynthesis

2012 ◽  
Vol 13 (11) ◽  
pp. R105 ◽  
Author(s):  
Simon E Alfred ◽  
Anuradha Surendra ◽  
Chris Le ◽  
Ken Lin ◽  
Alexander Mok ◽  
...  
Keyword(s):  
Chlamydomonas Reinhardtii ◽  
Small Molecule ◽  
Phenotypic Screening ◽  
Screening Platform ◽  
Small Molecule Modulators

scholarly journals A phenotypic screening platform utilising human spermatozoa identifies compounds with contraceptive activity

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Franz S Gruber ◽  
Zoe C Johnston ◽  
Christopher LR Barratt ◽  
Paul D Andrews
Keyword(s):  
Drug Discovery ◽  
Target Identification ◽  
Human Sperm ◽  
Phenotypic Screening ◽  
Major Barrier ◽  
Drug Candidates ◽  
Critical Gap ◽  
Comprehensive Collection ◽  
Screening Platform ◽  
Novel Drug

There is an urgent need to develop new methods for male contraception, however a major barrier to drug discovery has been the lack of validated targets and the absence of an effective high-throughput phenotypic screening system. To address this deficit, we developed a fully-automated robotic screening platform that provided quantitative evaluation of compound activity against two key attributes of human sperm function: motility and acrosome reaction. In order to accelerate contraceptive development, we screened the comprehensive collection of 12,000 molecules that make up the ReFRAME repurposing library, comprising nearly all the small molecules that have been approved or have undergone clinical development, or have significant preclinical profiling. We identified several compounds that potently inhibit motility representing either novel drug candidates or routes to target identification. This platform will now allow for major drug discovery programmes that address the critical gap in the contraceptive portfolio as well as uncover novel human sperm biology.

scholarly journals HTiP: High-Throughput Immunomodulator Phenotypic Screening Platform to Reveal IAP Antagonists as Anti-cancer Immune Enhancers

2019 ◽  
Vol 26 (3) ◽  
pp. 331-339.e3 ◽  
Author(s):  
Xiulei Mo ◽  
Cong Tang ◽  
Qiankun Niu ◽  
Tingxuan Ma ◽  
Yuhong Du ◽  
...  
Keyword(s):  
High Throughput ◽  
Phenotypic Screening ◽  
Anti Cancer ◽  
Screening Platform
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