# Hydroxyproline Dehydrogenase Inhibitors for the Treatment of Primary Hyperoxaluria

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2024 · $674,480

## Abstract

PROJECT SUMMARY:
The breakdown of hydroxyproline, a component of collagen within our bodies and in the meat that we consume,
is a significant contributor to glyoxylate and oxalate levels. We have shown in normal individuals and patients
with primary hyperoxaluria (PH) that hydroxyproline is converted to oxalate (18% for PH1, 47% for PH3, and
33% for PH3). These values are the largest known contribution to oxalate formation for any metabolite studied
to date. We hypothesize that blocking the hydroxyproline pathway with a drug will significantly lower the
glyoxylate and oxalate burden of PH2 and PH3 patients, for which there are no available therapies. The target
of this study is the first enzyme in the hydroxyproline degradation pathway, hydroxyproline dehydrogenase
(HYPDH). A drug that blocks HYPDH activity would prevent the formation of downstream metabolites that
contribute to oxalate levels. This strategy is supported by the observation that individuals that are deficient in
HYPDH are normal and safely excrete the excess hydroxyproline into their urine. Our team has made the HYPDH
knockout mouse (Prodh2 gene) and shown that the mice are healthy and not affected by HYPDH deficiency.
Moreover, we have shown that the HYPDH knockout in the PH2 mouse model protects the mice from oxalate
production from hydroxyproline. Thus, inhibition of HYPDH shows promise for the prevention and treatment of
PH. Our team has already performed high throughput screening assays and identified potent inhibitors of
HYPDH. These inhibitors require further optimization to improve potency, selectivity, and drug-like properties.
The proposed research program will combine our biochemical, cellular, structural biology, computational, and
medicinal chemistry expertise to optimize the compounds. The following specific aims illustrate the iterative
compound progression plan that will be employed: (Aim 1) to design and synthesize compounds that will explore
the structure-activity-relationship (SAR) properties of HYPDH inhibitor scaffolds; (Aim 2) to determine the
biochemical and cellular properties of HYPDH inhibitors; (Aim 3) to apply computational and structural biology
approaches to determine the binding mode of HYPDH inhibitors to inform compound design and synthesis; and
(Aim 4) to determine the efficacy of HYPDH inhibitors in a variety of PH mouse models.

## Key facts

- **NIH application ID:** 10868923
- **Project number:** 1R01DK137305-01A1
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** W TODD LOWTHER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $674,480
- **Award type:** 1
- **Project period:** 2024-08-16 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868923

## Citation

> US National Institutes of Health, RePORTER application 10868923, Hydroxyproline Dehydrogenase Inhibitors for the Treatment of Primary Hyperoxaluria (1R01DK137305-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10868923. Licensed CC0.

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