# Peripheral membrane proteins and disease: tool development, basic investigations, and inhibitor design

> **NIH NIH R35** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $388,125

## Abstract

Abstract
Peripheral membrane proteins (PMPs) represent crucial mediators of biological and disease processes. This
class of proteins exists in a water-soluble state until targeted to adhere on membranes, enabling them to
perform their function. As with any membrane associated protein, PMPs are challenging to study, particularly in
their membrane bound state, leaving many basic questions about function unresolved. Additionally, utilizing
PMPs as drug targets is difficult since current methods are designed for water-soluble proteins and do not work
well for membrane associated proteins. Thus, there is a great need for novel tools and procedures to illuminate
details of PMP function and to create PMP inhibitors for use in chemical biology study and as drug leads. The
goal of our research is to enable high-resolution, quantitative study of PMP interactions and allow inhibitor
design for this elusive type of protein. We will initially focus our efforts on three PMPs of extraordinary
biomedical interest: glutathione peroxidase 4 (GPx4) and Phox homology (PX) domains in the NADPH oxidase
family (p47phox-PX and NOXO1-PX). We have initiated development of a novel membrane model, membrane-
mimicking reverse micelles (mmRMs), which is based on the chemistry of cellular membranes. PMPs embed
into mmRMs as they do with cellular membranes, enabling high-resolution study using NMR spectroscopy and
other techniques. mmRMs have a number of advantages over current models, including greatly enhanced
stability, outstanding spectroscopic properties, and an ability to house high concentrations of analyte along with
the protein. We will modify our mmRM system to better reflect a variety of cellular and organelle membranes,
allowing the system to be tuned according to the natural PMP environment. Our focus will then be to harness
the unique properties of our mmRMs to enable unrivaled detail in study and quantification of PMP interactions
with membranes and lipid substrates. To facilitate inhibitor design, we will develop a novel method that allows
fragment screening of membrane-embedded PMPs, for which current methods are not suitable. Using these
tools, we will initiate an inhibitor design campaign for our important PMP targets. Overall, our goal is to develop
tools that will enable breakthroughs in detailed study of PMP biology as well as inhibitor and drug development
for this largely untapped class of proteins.

## Key facts

- **NIH application ID:** 10894206
- **Project number:** 5R35GM147221-03
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Brian Fuglestad
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,125
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894206

## Citation

> US National Institutes of Health, RePORTER application 10894206, Peripheral membrane proteins and disease: tool development, basic investigations, and inhibitor design (5R35GM147221-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10894206. Licensed CC0.

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