Discovery of novel trifunctional hybrid compounds (tfhcs): potential glaucoma therapy with superior IOP reduction and neuroprotection

The National Eye Institute, part of the National Institutes of Health within the Department of Health and Human Services, awarded Creighton University $350,000 on September 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to support discovery and development of novel trifunctional hybrid compounds for glaucoma therapy.

The funded research focuses on designing and evaluating trifunctional hybrid compounds that integrate three disease-modifying entities—an FP receptor agonist, a nitric oxide donor, and a hydrogen sulfide releasing moiety—to simultaneously address elevated intraocular pressure and glaucomatous neurodegeneration. The work builds on a lead molecule, AMP249, with particular emphasis on a derivative compound, JDB023, which demonstrated sustained release of nitric oxide and hydrogen sulfide in vitro (exceeding 15 days), superior intraocular pressure-lowering activity in vivo, and neuroprotection in ex vivo models. The research employs structure-activity relationship approaches to optimize compound stability and efficacy, with proposed mechanisms involving FP receptor activation and modulation of cGMP and KAtp signaling pathways to drive extracellular matrix remodeling and reduce oxidative stress.

Performance occurs in Omaha, Nebraska. The award runs from September 1, 2026, through July 31, 2031. The assistance type is a Project Grant.

Abstract

/summary glaucoma is one of the leading causes of irreversible vision loss and blindness globally, affecting over 80 million people. Current treatments primarily aim to reduce intraocular pressure (IOP), which is the main modifiable risk factor in the development and progression of the disease. However, despite pharmacological or surgical interventions, many patients continue to experience progressive vision loss. IOP-lowering therapies do not directly address the underlying neurodegenerative processes involved in glaucomatous damage, and patients may develop resistance to these treatments over time. A recent example, the FDA-approved BI-functional hybrid drug LBN (latanoprost bonded to a nitric oxide [no] donor via a hydrolyzable ester linkage), provides IOP- lowering benefits but loses its neuroprotective potential upon hydrolysis in the anterior segment of the eye. This highlights the urgent need for more effective therapeutic approaches. Our research is focused on developing novel trifunctional hybrid compounds (tfhcs) that integrate three disease-modifying entities: an FP receptor agonist, a no donor, and a hydrogen sulfide (H₂S) releasing moiety, all linked via a biocompatible spacer. These compounds are designed to simultaneously target elevated IOP and glaucomatous neurodegeneration. Using a structure-activity relationship (SAR) approach based on our lead molecule AMP249, we replaced its labile ester bond with a stable, non-hydrolyzable amide to create JDB023. This compound demonstrated sustained no and H₂S release (>15 days) in vitro, superior IOP-lowering activity in vivo, and neuroprotection in EX vivo models. We propose that JDB023 activates FP receptors and modulates the cgmp and katp signaling pathways, contributing to extracellular matrix (ECM) remodeling and reduction of oxidative stress. Importantly, JDB023 also targets intersecting pathogenic pathways such as BMP/TGFΒ2/SMAD1/2, thereby offering both anterior (IOP reduction) and posterior (retinal neuroprotection) therapeutic benefits. Building on these promising findings, our objectives are threefold. First, we will design and synthesize new tfhcs by optimizing the AMP249 scaffold using SAR strategies. These compounds will be screened in vitro for high and sustained no and H₂S release to identify 20 lead candidates, which will then undergo in vivo IOP- lowering and cytotoxicity testing to select two non-toxic compounds for pharmacokinetic profiling (aim 1). Next, we will investigate the functional roles of the three tfhc components; FP receptor agonist, no, and H₂S, by evaluating their individual and combined effects on IOP reduction, elucidating the mechanisms of TGF- Β2/SMAD2/3-induced trabecular meshwork fibrosis, and assessing the influence of glutathione on compound activity (aim 2). Finally, we will evaluate the neuroprotective efficacy of JDB023 and the two selected tfhc candidates in a new zealand albino rabbit model of ocular hypertension (aim 3).