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The antagonism of folate receptor by dolutegravir

developmental toxicity reduction by supplemental folic acid

Cabrera, Robert M.a; Souder, Jaclyn P.a,b; Steele, John W.a; Yeo, Lythoua; Tukeman, Gabriela; Gorelick, Daniel A.a; Finnell, Richard H.a,c

doi: 10.1097/QAD.0000000000002289
BASIC SCIENCE
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Objective: Maternal folate (vitamin B9) status is the largest known modifier of neural tube defect risk, so we evaluated folate-related mechanisms of action for dolutegravir (DTG) developmental toxicity.

Design: Folate receptor 1 (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 noncompetitive FOLR1 antagonist at therapeutic concentrations. In-vitro testing indicates calcium (2 mmol/l) increases FOLR1-folate interactions and alters DTG-FOLR1-folate interactions and cytotoxicity. DTG does not inhibit downstream folate metabolism by dihydrofolate reductase. 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 neural tube defects, 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 antiretroviral therapy in women of childbearing age.

aDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas

bMedical Scientist Training Program, University of Alabama at Birmingham, Birmingham, Alabama

cBaylor of Medicine, Baylor College of Medicine, Houston, Texas, USA.

Correspondence to Robert M. Cabrera, PhD, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA. E-mail: Robert.Cabrera@bcm.edu

Received 20 March, 2019

Revised 14 June, 2019

Accepted 21 June, 2019

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Copyright © 2019 Wolters Kluwer Health, Inc.