Animal cell membranes are like vast oceans where phospholipids are “water” and clusters of other specialized lipids, carbohydrates, and proteins are “rafts” floating about. These lipid rafts help cells maintain order within their membranes, which plays an integral role in cellular function.
A recent paper from the lab of Charles Sanders, the Aileen M. Lange and Annie Mary Lyle Professor of Cardiovascular Research and a professor of biochemistry, describes the discovery of two small molecules that can affect the stability of these rafts, which will help researchers study their function.
We checked in with Sanders, who told us more about the research.
What issue/problem does your research address?
This paper in Proceedings of the National Academy of Sciences and another paper we published recently in Communications Chemistry describe a set of first-in-class compounds that modulate lipid raft formation in biological membranes, sometimes in a protein-dependent manner. Some of these compounds also modulate the association of certain membrane proteins with lipid rafts and the activity of certain proteins in live cells.
What was unique about your approach to the research?
This project was started at Vanderbilt in my lab and the lab of Anne Kenworthy (before she moved to the University of Virginia) and was originally supported by a Stanley Cohen Innovation Fund grant in 2016. The membrane biochemistry and biophysics expertise of these two labs, combined with our excellent High-Throughput Screening Facility, made Vanderbilt an ideal place for this work.
What were your top findings?
We developed an HTS platform for discovering molecules that alter either lipid raft formation or the partitioning of membrane proteins into lipid rafts. We originally published this part in a 2022 ACS Central Science paper in which Anne was corresponding author. This set us up for the following results we described in the paper:
- We report the first-ever known discovery of compounds that modulate lipid rafts. Some of the modulation occurs in protein-dependent modes and some in protein-independent modes.
- We report the discovery of the first compounds that modulate the association of certain proteins with lipid rafts.
We found that a subset of the reported compounds modulates the activity of at least two proteins that are important to human health.
What do you hope will be achieved with the research results on the short term?
There are thousands of papers about lipid rafts, which are thought to be involved in a myriad of biological processes. Our work presents the first pharmacological agents for modulating their formation.
What are your highest translational/clinical aspirations that might come from this research?
Lipid rafts and protein association with lipid rafts are postulated to be relevant to many disease states. The compounds we have developed may provide the basis for testing hypotheses about how lipid rafts are involved in disease.
Where is this research taking you next? What will you personally be doing, or how will other researchers build on this work?
The first author of this paper, postdoctoral fellow Katherine Stefanski, is also the co-corresponding author. She will continue this project after she lands an academic job and sets up her own lab. She will use these compounds to develop new tools to investigate burning questions in membrane biology.
Who or what made the difference in your research? What small things contributed to your work?
This was a long, hard, project. I think patience and persistence were its defining traits! We really appreciate our collaborators: Anne Kenworthy from the University of Virginia, Wade Van Horn and his lab from Arizona State University, former Sanders grad student and now Yale postdoc James Hutchison, and Al George and his lab at Northwestern University. Without their contributions, this PNAS paper would never have reached the finish line.
Go deeper
The paper “Protein-enhanced small molecule disruptors of ordered membrane domains” was published in Proceedings of the National Academy of Sciences in June 2026.
Funding
This research used funds from the Vanderbilt Stanley Cohen Innovation Fund, the American Heart Association, the CMT Research Foundation, the National Heart, Lung, and Blood Institute, the National Institute of General Medical Sciences, and the National Institute of Neurological Disorders and Stroke.
School of Medicine Basic Sciences shared resources
This research made use of the Cell Imaging Shared Resource and the High-Throughput Screening Facility.
Open access
The study was published open access through a transformative agreement negotiated by Vanderbilt University’s Jean and Alexander Heard Libraries. Transformative agreements eliminate traditional paywalls and remove the obstacle of article processing charges, ensuring immediate and unrestricted access to research worldwide. Vanderbilt authors can learn more about the Heard Libraries’ agreements supporting open access publishing in this research guide.