1. Developmental Biology

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

  1. Franz S Gruber
  2. Zoe C johnston
  3. Christopher LR Barratt  Is a corresponding author
  4. Paul D Andrews
  1. University of Dundee, United Kingdom
https://doi.org/10.7554/eLife.51739
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  1. Franz S Gruber
  2. Zoe C johnston
  3. Christopher LR Barratt
  4. Paul D Andrews
(2020)
A phenotypic screening platform utilising human spermatozoa identifies compounds with contraceptive activity
eLife 9:e51739.
https://doi.org/10.7554/eLife.51739
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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.

Data availability

Full data is available. Large files have been deposited :https://datadryad.org/stash/share/06d75FZ6GiPmme3HnKnkyTFbgKJ2mV0UVRaN-gVKoVE.

The following data sets were generated

Article and author information

Author details

  1. Franz S Gruber

    School of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    No competing interests declared.

  2. Zoe C johnston

    Division of Systems Medicine, University of Dundee, Dundee, United Kingdom
    Competing interests
    No competing interests declared.

  3. Christopher LR Barratt

    Division of Systems Medicine, University of Dundee, Dundee, United Kingdom
    For correspondence
    c.barratt@dundee.ac.uk
    Competing interests
    Christopher LR Barratt, Editor for RBMO, has received lecturing fees from Merck, Pharmasure and Ferring and was on the Scientific Advisory Panel for Ohana BioSciences.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0062-9979

  4. Paul D Andrews

    School of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7699-5604

Funding

Bill and Melinda Gates Foundation (OPP1160989)

  • Zoe C johnston

Bill and Melinda Gates Foundation (OPP1203050)

  • Franz S Gruber
  • Zoe C johnston
  • Christopher LR Barratt
  • Paul D Andrews

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The Funders did facilitate using the REFRAME library

Reviewing Editor

  1. Polina V Lishko, University of California, Berkeley, United States

Ethics

Human subjects: Written consent was obtained from each donor in accordance with the Human Fertilization and Embryology Authority (HFEA) Code of Practice (version 8) under local ethical approval (13/ES/0091) from the Tayside Committee of Medical Research Ethics B.

Version history

  1. Received: September 9, 2019
  2. Accepted: January 19, 2020
  3. Accepted Manuscript published: January 28, 2020 (version 1)
  4. Version of Record published: February 27, 2020 (version 2)

Copyright

© 2020, Gruber et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Franz S Gruber
  2. Zoe C johnston
  3. Christopher LR Barratt
  4. Paul D Andrews
(2020)
A phenotypic screening platform utilising human spermatozoa identifies compounds with contraceptive activity
eLife 9:e51739.
https://doi.org/10.7554/eLife.51739

Share this article

https://doi.org/10.7554/eLife.51739

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    The MODY-associated KCNK16 L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

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    The gain-of-function mutation in the TALK-1 K+ channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and β-cell-restricted K+ channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1 (ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.