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

Franz S. Gruber, Zoe C. Johnston, Christopher L. R. Barratt (Lead / Corresponding author), Paul D. Andrews

Research output: Contribution to journalArticle

4 Downloads (Pure)

Abstract

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.
Original languageEnglish
Article numbere51739
JournaleLife
Volume9
DOIs
Publication statusE-pub ahead of print - 28 Jan 2020

Fingerprint

Drug Discovery
Contraceptive Agents
Spermatozoa
Screening
Acrosome Reaction
Molecules
Sperm Motility
Robotics
Contraception
Libraries
Throughput
Pharmaceutical Preparations

Keywords

  • Drug discovery
  • Sperm motility
  • phenotypic screening
  • acrosome reaction
  • spermatozoa
  • contraception

Cite this

@article{a1b34f9b45af4ae197d722e04b50a4ab,
title = "A phenotypic screening platform utilising human spermatozoa identifies compounds with contraceptive activity",
abstract = "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.",
keywords = "Drug discovery, Sperm motility, phenotypic screening, acrosome reaction, spermatozoa, contraception",
author = "Gruber, {Franz S.} and Johnston, {Zoe C.} and Barratt, {Christopher L. R.} and Andrews, {Paul D.}",
note = "Funding was provided by Bill and Melinda Gates Foundation. CLRB also receives funding from Chief Scientists Office (Scotland) and Astra Zeneca PLC. NPSC was established with funding from the Scottish Funding Council and Scottish Universities Life Science Alliance. PDA/NPSC receives funding from Janssen Pharmaceutica NV.",
year = "2020",
month = "1",
day = "28",
doi = "10.7554/eLife.51739",
language = "English",
volume = "9",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications Ltd.",

}

TY - JOUR

T1 - A phenotypic screening platform utilising human spermatozoa identifies compounds with contraceptive activity

AU - Gruber, Franz S.

AU - Johnston, Zoe C.

AU - Barratt, Christopher L. R.

AU - Andrews, Paul D.

N1 - Funding was provided by Bill and Melinda Gates Foundation. CLRB also receives funding from Chief Scientists Office (Scotland) and Astra Zeneca PLC. NPSC was established with funding from the Scottish Funding Council and Scottish Universities Life Science Alliance. PDA/NPSC receives funding from Janssen Pharmaceutica NV.

PY - 2020/1/28

Y1 - 2020/1/28

N2 - 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.

AB - 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.

KW - Drug discovery

KW - Sperm motility

KW - phenotypic screening

KW - acrosome reaction

KW - spermatozoa

KW - contraception

U2 - 10.7554/eLife.51739

DO - 10.7554/eLife.51739

M3 - Article

VL - 9

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e51739

ER -