PUBLICATION
The antagonism of folate receptor by dolutegravir: developmental toxicity reduction by supplemental folic acid
- Authors
- Cabrera, R.M., Souder, J.P., Steele, J.W., Yeo, L., Tukeman, G., Gorelick, D.A., Finnell, R.H.
- ID
- ZDB-PUB-190702-5
- Date
- 2019
- Source
- AIDS (London, England) 33(13): 1967-1976 (Journal)
- Registered Authors
- Gorelick, Daniel, Souder, Jaclyn P.
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Line
- Dietary Supplements
- Embryonic Development/drug effects
- Female
- Folate Receptor 1/antagonists & inhibitors*
- Folate Receptor 1/genetics
- Folic Acid/administration & dosage*
- HIV Infections/drug therapy
- HIV Integrase Inhibitors/toxicity
- Heterocyclic Compounds, 3-Ring/toxicity*
- Humans
- Models, Animal
- Pregnancy
- Toxicity Tests
- Zebrafish/embryology*
- Zebrafish/genetics
- Zebrafish Proteins/antagonists & inhibitors*
- Zebrafish Proteins/genetics
- PubMed
- 31259764 Full text @ AIDS
Citation
Cabrera, R.M., Souder, J.P., Steele, J.W., Yeo, L., Tukeman, G., Gorelick, D.A., Finnell, R.H. (2019) The antagonism of folate receptor by dolutegravir: developmental toxicity reduction by supplemental folic acid. AIDS (London, England). 33(13):1967-1976.
Abstract
Objective Maternal folate (vitamin B9) status is the largest known modifier of neural tube defect (NTD) risk, so we evaluated folate-related mechanisms of action for dolutegravir (DTG) developmental toxicity.
Design Folate receptor (FOLR1) was examined as a target for DTG developmental toxicity using protein and cellular interaction studies and an animal model.
Methods FOLR1 competitive binding studies were used to test DTG for FOLR1 antagonism. Human placenta cell line studies were used to test interactions with DTG, folate, and cations. Zebrafish were selected as an animal model to examine DTG-induced developmental toxicity and rescue strategies.
Results FOLR1 binding studies indicate DTG is a non-competitive FOLR1 antagonist at therapeutic concentrations. In vitro testing indicates calcium (2 mM) 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.
Conclusion Folates and FOLR1 are established modifiers of risk for NTDs, and binding data indicates DTG is a partial antagonist of FOLR1. Supplemental folate can ameliorate increased developmental toxicity due to DTG in zebrafish. 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.
Errata / Notes
This article is corrected by ZDB-PUB-220906-235 .
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping