Biology subjects

Barratt, C. L.

Publications and source records attributed to Barratt, C. L..

4 recordsLinked to original sources

bioRxiv2023

Sperm Toolbox - A selection of small molecules to study human spermatozoa

Male contraceptive options and infertility treatments are limited. To help overcome these limitations we established a small molecule library as a toolbox for assay development and screening campaigns using human spermatozoa. We have profiled all compounds in our automated high-throughput screening platform and provide the dataset, which allows direct side-by-side comparisons of compound effects and assays using live human spermatozoa.

pharmacology and toxicology↗

bioRxiv2021

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

Study 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 field Study 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.

physiology↗

bioRxiv2021

Research Funding for Male Reproductive Health and Infertility in the UK and USA

TitleResearch Funding for Male Reproductive Health and Infertility in the UK and USA [2016 - 2019] Study questionWhat is the research funding for male reproductive health and infertility in the UK and US between 2016 to 2019? Summary answerThe average funding for a research project in male reproductive health and infertility was not significantly different to that for female-based projects ({pound}653,733 in the UK and $779,707 in the US). However, only 0.07% and 0.83% of government funds from NIHR (UK) and NICHD (USA) was granted for male reproductive health, respectively. What is known alreadyThere is a marked paucity of data on research funding for male reproductive health. Study design, size, durationExamined government databases over a total 4-year period from January 2016 to December 2019. Participants/materials, setting, methodsInformation on the funding provided to male-based and female-based research was collected using public accessed web-databases from the UKRI-GTR, the NIHRs Open Data Summary, and the US NIH RePORT. Funded projects that began research activity between January 2016 to December 2019 were recorded, along with their grant and project details. Strict inclusion-exclusion criteria were followed for both UK and US data with a primary research focus of male infertility, reproductive health and disorders, and contraception development. Funding support was divided into three research groups: male-based, female-based, and not-specified research. Between the 4-year period, the UK is divided into 5 funding periods, starting from 2015/16 to 2019/20, and the US is divided into 5 fiscal years, from 2016 to 2020. Main results and the role of chanceBetween January 2016 to December 2019, UK agencies awarded a total of {pound}11,767,190 to 18 projects for male-based research and {pound}29,850,945 to 40 projects for female-based research. There was no statistically significant difference in funding average between the two research groups (P=0.56, W=392). The US NIH funded 76 projects totaling $59,257,746 for male-based research and 99 projects totaling $83,272,898 for female-based research. There was no statistically significant difference in funding average between the two groups (P=0.83, W=3834). Limitations, reasons for cautionThe findings of this study cannot be used to generalize and reflect global funding trends towards infertility and reproductive health as the data collected followed a narrow funding timeframe from government agencies and only two countries. Other funding sources such as charities, industry and major philanthropic organizations were not evaluated. Wider implications of the findingsThis is the first study examining funding granted by main government research agencies from the UK and US for male reproductive health. This study should stimulate further discussion of the challenges of tackling male infertility and reproductive health disorders and formulate appropriate investment strategies. Study funding/competing interest(s)CLRB is Editor for RBMO and has received lecturing fees from Merck, Pharmasure, and Ferring. His laboratory is funded by Bill and Melinda Gates Foundation, CSO, Genus. No other authors declare a conflict of interest.

scientific communication and education↗

bioRxiv2019

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

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.

developmental biology↗