# Directed evolution of tissue inhibitor of metalloproteinase 3 (TIMP-3) to develop novel Alzheimer’s disease (AD) therapeutics

> **NIH NIH R03** · UNIVERSITY OF NEVADA RENO · 2022 · $299,975

## Abstract

SUMMARY
Limited efficient therapeutics are available to control Alzheimer's disease (AD), so there is a strong demand to
target new pathogenic biomarkers of AD. The metzincin superfamily, including matrix metalloproteinases
(MMPs) and a disintegrin and metalloproteinases (ADAMs), play a multifaceted role in physiological and
pathological processes in the central nervous system and therefore are therapeutic targets to limit
neurodegeneration in AD. For instance, upregulation of MMP-9 promotes apoptosis, blood-brain barrier
disorder, and demyelination and is involved in the amyloid-β processing pathway through proteolytic
degradation of extracellular matrix components and tissue remodeling, and increasing tau accumulation which
play key roles in AD. But on the other hand, upregulation of ADAM-10 increases soluble amyloid-β formation,
which helps control AD. Thus, using highly selective inhibitors to tailor the proteolytic activity of metzincin-
induced pathological changes in AD patients’ brains may be a promising therapeutic strategy. Protein inhibitors
offer higher selectivity to target MMP-9 compared to smaller synthetic inhibitory molecules with broad-spectrum
targets. Tissue inhibitors of metalloproteinases (TIMPs) are the major endogenous inhibitors of MMPs and
ADAMs with varying degrees of binding affinity. Among all TIMPs, TIMP-3 has the lowest association with the
cell signaling molecules triggering undesired off-target effect such as the ones responsible in tumorigenesis,
suggesting that it has a low off-target therapeutic effect in MMP-dependent diseases. This makes TIMP-3 an
ideal protein scaffold for engineering improved inhibitors for MMP-9. However, TIMP-3 also binds to other
MMPs, ADAMs, and growth factors. Here, we propose to use a combination of rational and random
combinatorial approaches to develop TIMP-3-based therapeutics to control neurodegenerative disease
progression by targeting MMP-9 with high selectivity. These engineered TIMP-based probes will avoid binding
to ADAM-10, which is neuroprotective in AD, to decrease off-target effects. The overarching goal of this project
is to engineer and design a new molecularly targeted therapy based on natural MMP inhibitors that target
MMP-9 with high selectivity, understand their mechanism of inhibition using structural studies and cell culture
models to improve outcomes in neurodegenerative diseases with inadequate treatment options.

## Key facts

- **NIH application ID:** 10303777
- **Project number:** 1R03AG070511-01A1
- **Recipient organization:** UNIVERSITY OF NEVADA RENO
- **Principal Investigator:** Maryam Raeeszadeh Sarmazdeh
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $299,975
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10303777

## Citation

> US National Institutes of Health, RePORTER application 10303777, Directed evolution of tissue inhibitor of metalloproteinase 3 (TIMP-3) to develop novel Alzheimer’s disease (AD) therapeutics (1R03AG070511-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10303777. Licensed CC0.

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