# Functional mechanism underlying Dolutegravir (DTG)-associated developmental CNS abnormalities: Inhibition of matrix metalloproteinases activities

> **NIH NIH R21** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $230,250

## Abstract

Project Summary
Background: Dolutegravir (DTG), an integrase strand transfer inhibitor (INSTI), currently recommended as both,
first-line therapy and part of either switching or salvage regimens for the treatment of human immunodeficiency
virus type-1 (HIV-1) infected patients. Due to the roll out of generic DTG-based regimen and its inclusion in
national treatment guidelines in resource limited countries (RLCs), in just 5 years, 15 million HIV-1 infected
people will be treated with DTG. This includes women of child-bearing age, who remain a significant infected
population (UNAIDS data, 2020). However, during recent years, growing data from different clinical and pre-
clinical studies have suggested that the DTG is associated with birth defects and with postnatal developmental
neurologic abnormalities. Thus, concerns emerged for the usage of DTG-based regimens in pregnant women or
those of child-bearing age. Knowledge gap: While clinical cohort studies identified risk of neurologic
abnormalities in babies following in utero DTG-exposure, underlying mechanism for DTG-associated
developmental neurotoxicity, particularly in babies born without structural, brain or spinal cord, malformations
remains unknown. Our preliminary data: DTG was found to be a broad-spectrum inhibitor of MMPs. The drug
was found to bind Zn++ at the catalytic domain, leading to inhibition of MMPs activities. Moreover, studies in
pregnant mice showed that DTG can cross the placental barrier, accumulate in the fetal central nervous system
(CNS) and inhibit MMPs activity during the critical period of fetal brain development. Further postnatal evaluation
of brain health in mice pups following in utero DTG exposures identified neuroinflammation and neuronal
damage. These data demonstrated an association between DTG dysregulation of MMPs activities during
gestation and consequent neurotoxicity. Hypothesis: We hypothesize that DTG inhibition of MMPs activities
during gestation impairs neurodevelopment. Research Strategy: (1) Determine dose-dependent enzyme
inhibition kinetics of different drugs from INSTI class, which include DTG, bictegravir (BIC) and cabotegravir
(CAB). (2) Determine longitudinal dose-dependent affect of DTG on MMPs function and expression in embryo
CNS during gestation. (3) Identify the impact of MMPs inhibition by DTG on embryo neurodevelopmental
physiological processes (angiogenesis and neurogenesis) during pregnancy. (4) Evaluate whether BIC and CAB
also affect the MMPs activities and associated neurodevelopmental processes in vivo through same mechanism
to assess the class effect. Research Team: We have assembled a multidisciplinary team with expertise in
neuropathology, immunology, pharmaceutics, virology, and bioimaging to evaluate impact of in utero DTG and
of other drugs from INSTI class exposure on the embryo brain development. Outcome: Successful outcome of
the proposal will significantly advance the field in understanding the theory of DTG inhibition of...

## Key facts

- **NIH application ID:** 10491979
- **Project number:** 5R21HD106842-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Aditya N Bade
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $230,250
- **Award type:** 5
- **Project period:** 2021-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491979

## Citation

> US National Institutes of Health, RePORTER application 10491979, Functional mechanism underlying Dolutegravir (DTG)-associated developmental CNS abnormalities: Inhibition of matrix metalloproteinases activities (5R21HD106842-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10491979. Licensed CC0.

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