Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

The Antagonism of Folate Receptor by the Integrase Inhibitor Dolutegravir: Developmental Toxicity Reduction by Supplemental Folic Acid

View ORCID ProfileRobert M. Cabrera, Jaclyn P. Souder, John W. Steele, Lythou Yeo, Gabriel Tukeman, View ORCID ProfileDaniel A. Gorelick, View ORCID ProfileRichard H. Finnell
doi: https://doi.org/10.1101/576272
Robert M. Cabrera
1Baylor College of Medicine, Department of Molecular and Cellular Biology, Houston, TX
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Robert M. Cabrera
  • For correspondence: Robert.Cabrera@bcm.edu
Jaclyn P. Souder
1Baylor College of Medicine, Department of Molecular and Cellular Biology, Houston, TX
2University of Alabama at Birmingham, Medical Scientist Training Program, Birmingham, AL
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John W. Steele
1Baylor College of Medicine, Department of Molecular and Cellular Biology, Houston, TX
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lythou Yeo
1Baylor College of Medicine, Department of Molecular and Cellular Biology, Houston, TX
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gabriel Tukeman
1Baylor College of Medicine, Department of Molecular and Cellular Biology, Houston, TX
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel A. Gorelick
1Baylor College of Medicine, Department of Molecular and Cellular Biology, Houston, TX
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Daniel A. Gorelick
Richard H. Finnell
1Baylor College of Medicine, Department of Molecular and Cellular Biology, Houston, TX
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Richard H. Finnell
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

ABSTRACT

Human immunodeficiency virus (HIV) integrase inhibitors are increasingly being used for antiretroviral therapy (ART), and dolutegravir (DTG/Tivicay) has emerged as a leading core agent. In 2018, the Tsepamo study reported a 6- to 9-fold increase for neural tube defect (NTD) risk among the offspring of mothers receiving DTG during early gestation. Maternal folate (vitamin B9) status is the largest known modifier of NTD risk, so we evaluated folate-related mechanisms of action and the critical period for DTG developmental toxicity. Folate receptor (FOLR1) binding studies indicate DTG is a non-competitive FOLR1 antagonist at therapeutic concentrations. In vitro testing indicates calcium (2mM) increases FOLR1-folate interactions and alters DTG-FOLR1-folate interactions and cytotoxicity. DTG does not inhibit downstream folate metabolism by dihydrofolate reductase (DHFR). Early embryonic exposure to DTG is developmentally toxic in zebrafish, and supplemental folic acid can mitigate DTG developmental toxicity. The results from these studies are expected to inform and guide future animal models and clinical studies of DTG-based ART in women of childbearing age.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted March 14, 2019.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
The Antagonism of Folate Receptor by the Integrase Inhibitor Dolutegravir: Developmental Toxicity Reduction by Supplemental Folic Acid
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
The Antagonism of Folate Receptor by the Integrase Inhibitor Dolutegravir: Developmental Toxicity Reduction by Supplemental Folic Acid
Robert M. Cabrera, Jaclyn P. Souder, John W. Steele, Lythou Yeo, Gabriel Tukeman, Daniel A. Gorelick, Richard H. Finnell
bioRxiv 576272; doi: https://doi.org/10.1101/576272
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
The Antagonism of Folate Receptor by the Integrase Inhibitor Dolutegravir: Developmental Toxicity Reduction by Supplemental Folic Acid
Robert M. Cabrera, Jaclyn P. Souder, John W. Steele, Lythou Yeo, Gabriel Tukeman, Daniel A. Gorelick, Richard H. Finnell
bioRxiv 576272; doi: https://doi.org/10.1101/576272

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Pharmacology and Toxicology
Subject Areas
All Articles
  • Animal Behavior and Cognition (4119)
  • Biochemistry (8828)
  • Bioengineering (6532)
  • Bioinformatics (23484)
  • Biophysics (11805)
  • Cancer Biology (9223)
  • Cell Biology (13336)
  • Clinical Trials (138)
  • Developmental Biology (7442)
  • Ecology (11425)
  • Epidemiology (2066)
  • Evolutionary Biology (15173)
  • Genetics (10453)
  • Genomics (14056)
  • Immunology (9187)
  • Microbiology (22199)
  • Molecular Biology (8823)
  • Neuroscience (47626)
  • Paleontology (351)
  • Pathology (1431)
  • Pharmacology and Toxicology (2493)
  • Physiology (3736)
  • Plant Biology (8090)
  • Scientific Communication and Education (1438)
  • Synthetic Biology (2224)
  • Systems Biology (6042)
  • Zoology (1254)