# Inhibition of Human Islet Amyloid Polypeptide Aggregation

> **NIH NIH R35** · CLEMSON UNIVERSITY · 2020 · $362,209

## Abstract

Abstract
Mounting evidence suggests that the aggregation of islet amyloid polypeptide (IAPP) is associated with β-cell
death in type-2 diabetes (T2D). IAPP, a 37-residue peptide hormone secreted by β-cells, readily forms amyloid
fibrils in vitro at µM concentrations. The aggregates of IAPP, either insoluble amyloid fibrils or soluble
oligomers, are found toxic to β-cells. Inhibition of IAPP aggregation is an attractive therapeutic strategy to
prevent β-cell death and stop the progression of diabetic conditions in T2D. Interestingly, no apparent IAPP
aggregates are observed in healthy individuals where IAPP is stored in β-cell granules at mM concentrations.
Therefore, physiological conditions of β-cell granules natively inhibit amyloid aggregation of IAPP. Disruption of
the inhibitive environment of β-cell granules may lead to the accumulation of toxic IAPP aggregates, causing β-
cell death and the diabetic condition of insulin deficiency in T2D. Molecular mechanisms of the native inhibition
of hIAPP aggregation are largely unknown, which limit the design of novel therapeutic approaches that either
promote or mimic the native inhibition. In addition, several naturally-occurring small-molecule polyphenols
displayed inhibitory effects on hIAPP aggregation. However, many of these small molecules have low water
solubility, which limits their bioavailability and biodistribution. Knowledge of the mechanism of action of these
polyphenols may help design de novo small-molecule drugs that can inhibit hIAPP aggregation with higher
efficacy and solubility. Further more, our preliminary studies combining in silico modeling with in vitro and ex
vivo characterization indicated that the generation-3 polyamidoamin (PAMAM) dendrimer, a polymeric
nanoparticle commonly used for drug delivery, could also inhibit hIAPP aggregation. Our results pointed to a
promising nanomedicinal approach for both efficient loading of ant-amyloid drug and inhibitory effect on hIAPP
aggregation. In this MIRA application, the PI proposes the following three projects to uncover various inhibition
mechanisms of hIAPP aggregation: 1) to delineate the inhibitive mechanism of the environmental elements of
granules on IAPP aggregation; 2) to uncover the inhibition mechanism of hIAPP aggregation by small-molecule
polyphenols; and 3) to explore dendritic nanoparticles with increased small-molecule loading and inhibitive
effects on hIAPP aggregation. The PI lab will combine computational modeling with experimental
characterization and validation. Computational modeling can help bridge the gaps of time and length scales
between experimental observations and the underlying molecular systems, providing not only molecular insight
to experimental observations but also offering experimentally-testable hypotheses. Such a combined
computational and experimental approach can improve research efficiency and shorten discovery cycle. The
outcome of the proposed studies will help design therapeutic strategie...

## Key facts

- **NIH application ID:** 9942473
- **Project number:** 5R35GM119691-05
- **Recipient organization:** CLEMSON UNIVERSITY
- **Principal Investigator:** Feng Ding
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,209
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942473

## Citation

> US National Institutes of Health, RePORTER application 9942473, Inhibition of Human Islet Amyloid Polypeptide Aggregation (5R35GM119691-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9942473. Licensed CC0.

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