# Small Molecule Tools for Modulating Membrane Rafts

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $397,145

## Abstract

Summary
Plasma membrane organization exerts tremendous influence on cellular functionality. A well known
mechanism underlying this organization is through nanoscopic clustering of distinct lipids and proteins in
membrane rafts. Raft domains are enriched in cholesterol and lipids with saturated acyl chains and share
properties with liquid-ordered membrane phases observed in vitro. In cell membranes, raft domains are
thought to co-exist with more fluid, disordered domains, and the cholesterol-rich environment of the plasma
membrane is thought to be especially conducive for raft formation. Individual membrane proteins tend to
prefer either raft or non-raft environments, and this propensity serves as an important regulatory mechanism of
their function. Further, raft-dependent processes have been implicated in many human pathologies including
several forms of cancer, AIDS and Alzheimer's disease. However, the size and dynamics of these domains
and how the partitioning of membrane proteins between ordered and disordered domains affect their functions
and interactions remain uncertain. We argue that these fundamental gaps in knowledge remain because few
methods exist to experimentally perturb rafts in a controlled manner. The objective of this proposal is
therefore to discover and validate first generation small molecules that can be used to
pharmacologically manipulate rafts. To tackle this problem, we have developed a novel high throughput
screen (HTS) assay exploiting giant plasma membrane vesicles (GPMVs) as a model system to visualize rafts
and their associated proteins, as well as custom software to quantitate these datasets. Using these
approaches, we have now identified several examples of bioactive lipids and FDA-approved drugs that alter
the relative proportions of ordered and disordered phases in GPMVs, as well as have preliminary evidence in
hand that suggests it is possible to alter the phase partitioning of selected membrane proteins. Here, we
propose to build on these initial successes to move from proof-of-principle stage to the point where we have in
hand validated first generation small molecules with these activities. Protein targets will include peripheral
myelin protein 22, a protein associated with Charcot-Marie-Tooth syndrome, and the HIV receptor CD4 and its
co-receptor CCR5. Ultimately, the results of these studies will lay the groundwork for the development of a
new class of chemicals that can be used to pharmacologically manipulate rafts in the laboratory and definitively
test long-standing questions about the nature of rafts as well as for employment in drug discovery programs.

## Key facts

- **NIH application ID:** 10029455
- **Project number:** 1R01GM138493-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Anne K Kenworthy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,145
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10029455

## Citation

> US National Institutes of Health, RePORTER application 10029455, Small Molecule Tools for Modulating Membrane Rafts (1R01GM138493-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10029455. Licensed CC0.

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