# Structural and biological characterization of a novel pan-amyloid, protofibril capping protein for the rational design of therapeutics that target age related amyloidosis syndromes

> **NIH NIH R21** · ROCKEFELLER UNIVERSITY · 2020 · $254,250

## Abstract

Project Summary
 
 Age is universally regarded as the primary risk factor in most amyloid-related disease syndromes.
There is a significant unmet need for novel, disease-modifying therapeutic strategies to target
amyloidosis syndromes. In CNS diseases such as Alzheimer's disease and Parkinson's disease, and in
systemic diseases such as Senile Systemic Amyloidosis and Light-chain Amyloidosis, disease-specific
proteins misfold to acquire a pathological cross-β-sheet conformation characteristic of amyloidosis.
Although the molecular pathophysiology of amyloid varies depending on the specific disease state, it is
a common shared feature that properly folded amylogenic proteins or peptides with important
physiological function become highly toxic upon misfolding. Interestingly, despite a lack of primary
structure homology, amyloid proteins share this common cross-β-sheet secondary structure and similar
quaternary structure when they misfold and aggregate.
 Molecular chaperones are naturally occurring inhibitors of amyloid protein aggregation, and
understanding their detailed biochemistry could substantially advance the development of new
treatments. Some chaperone-like amyloid binding proteins (CLABPs) can target amyloids from multiple
sources and therefore are hypothesized to make use of the common cross-β-sheet secondary
structures. These CLABPs display so-called pan-amyloid activity. However, only a small number of
pan-amyloid CLABPs have been identified to date, and even fewer target soluble, early aggregates
such as protofibrils. The molecular interactions between CLABPs and transient protofibrils remain
unknown, constituting a major obstacle for the development of high affinity pan-amyloid therapeutics.
 To address this problem, the naturally occurring CLABP, NUCB1, will be thoroughly investigated. To
date, this is the only CLABP that has pan-amyloid, protofibril capping activity. Using domain and
mutational analyses, the critical components that are necessary and sufficient for NUCB1 to cap
protofibrils will be defined. Understanding the NUCB1 capping mechanism will provide a unique
opportunity to develop an innovative approach to prevent the formation of toxic amyloid protofibril
conformations in human disease states. A NUCB1-immunoglobulin fusion protein will be engineered
that retains pan-amyloid, protofibril binding activity. This proof-of-concept molecule has potentially
impactful use as a tool for detecting protofibrils in situ, or ex vivo, and will be tested as a novel
therapeutic strategy in models of age-related amyloidosis syndromes.
 In summary, the extraordinary properties of the naturally occurring CLABP, NUCB1, will be exploited
to create a novel biotherapeutic that can “cap” and detoxify amyloid protofibrils derived from many
different amyloidogenic proteins and peptides associated with human diseases of aging.

## Key facts

- **NIH application ID:** 9852939
- **Project number:** 5R21AG061605-02
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** THOMAS P SAKMAR
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $254,250
- **Award type:** 5
- **Project period:** 2019-02-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852939

## Citation

> US National Institutes of Health, RePORTER application 9852939, Structural and biological characterization of a novel pan-amyloid, protofibril capping protein for the rational design of therapeutics that target age related amyloidosis syndromes (5R21AG061605-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9852939. Licensed CC0.

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