Brian Fuglestad investigates fundamental questions surrounding membrane associated proteins, while using this knowledge to approach these proteins as drug targets. Peripheral membrane proteins in particular are difficult to study in their functionally relevant, membrane-bound state. Dr. Fuglestad seeks to remedy this by developing new tools and methods to better understand these proteins. His work has demonstrated that proteins in this class may be inhibitable using small molecules to block interactions with lipids and membranes, opening a significant fraction of the human genome to potential druggability. With a particular focus on cancer and other disease-related peripheral membrane proteins, Dr. Fuglestad’s work provides a new approach to access these otherwise difficult-to-drug protein targets.
Dr. Fuglestad earned his B.S. in Biochemistry from Oklahoma State University. He continued his studies at the University of California, San Diego. He earned his Ph.D. in Chemistry, with a focus on biochemistry and biophysics, under the supervision of Dr. Elizabeth Komives in 2013. His thesis work examined the role of protein dynamics in the function of the blood coagulation factor thrombin. He subsequently joined Dr. Josh Wand’s group in the Department of Biochemistry & Biophysics at the Univeristy of Pennsylvania’s Perelman School of Medicine as a postdoctoral fellow. Here he specialized in developing and applying methods to enhance biophysical study and drug discovery for proteins that are otherwise difficult to access. He began his independent career as an assistant professor at Virginia Commonwealth University in 2019. He earned tenure and was promoted to associate professor in 2025. Dr. Fuglestad joined the Wistar Institute as an associate professor in 2026, as a member of the Center for Advanced Therapeutics.
The Fuglestad Laboratory
The Fuglestad Laboratory
The Fuglestad lab is interested in expanding molecular study of peripheral membrane proteins and enabling new strategies in drug development for this difficult category of protein. Their approach is rooted in detailed structural and biophysical investigation of fundamental protein function, information that is used to better understand peripheral membrane proteins as drug targets and to guide inhibitor design efforts. In addition, the Fuglestad group develops new tools and methods to enhance the ability to better study peripheral membrane proteins and initiate drug discovery for these elusive targets. The Fuglestad lab has developed a unique membrane model, membrane-mimicking reverse micelles, which allow access to experiments that are otherwise difficult or impossible for this class of protein. Protein targets of interest to the Fuglestad lab include glutathione peroxidase 4, an important cancer target, p47phox, which is implicated in a variety of inflammatory and other diseases, and a range of lipid transport proteins which are fundamental to lipid organization in the cell, many of which are important therapeutic targets. The unique tools and approaches that the Fuglestad lab utilizes has answered important functional questions surrounding these proteins. Their work has demonstrated unique inhibition strategies that may help peripheral membrane proteins become more routine targets for drug discovery.
Develin A., Fuglestad B. Inositol Hexaphosphate as an Inhibitor and Potential Regulator of p47phox Membrane Anchoring. Biochemistry. 2024, 63(9):1097–1106. (Featured on the Front Cover)
The membranes of a cell are hotspots of biological activity. In turn, many diseases proceed through action within or involving cellular membranes. Peripheral membrane proteins interact with membranes, often reversibly, to perform a variety of functions. Lipid transport proteins shuttle lipid between membranes. Technical and methodological limitations have hindered a full understanding of these classes of proteins in their functional, membrane-adhered states. We are interested in structural biology, biophysical and functional study of these proteins. This information is used to inform rational drug design efforts to block the disease-causing action of these proteins. The ultimate goal of the Fuglestad lab is to enhance our understanding of peripheral membrane and lipid transport proteins, inhibit them for chemical biology investigations, and to develop drugs to treat disease such as cancer and cardiovascular disorders.
New tools to study protein interactions with membranes and lipids
Understanding the interactions between peripheral membrane proteins and lipids is of paramount importance in strategizing therapeutics. We use a number of models of biological membranes to probe the interactions between proteins and cellular membranes. Of particular expertise in the Fuglestad lab is leveraging reverse micelles as membrane mimics, which has several advantages over other more commonly used membrane models. Recent developments have moved reverse micelles closer to the chemistry found in cellular membranes, allowing more physiologically relevant studies of protein interactions with membranes. We employ a multitude of techniques to study protein/membrane interactions including protein nuclear magnetic resonance (NMR) spectroscopy, MD simulations, fluorescence, and small-angle scattering, among others.
Walters SH, Signorelli RL, Payne AG, Hojjatian A, Fuglestad B. Compositional versatility enables biologically inspired reverse micelles for study of protein-membrane interactions. Soft Matter, 2025, 21, 3547-3557.
Inhibitor design for peripheral membrane proteins
Labrecque CL, Fuglestad B. Ligandability at the membrane interface of GPx4 revealed through a reverse micelle fragment screening platform. JACS Au. 2024, 4(7):2676-2686.
Rational design of inhibitors uses information about the structure and function of the protein target of interest. Fragment based inhibitor design is a powerful approach that is useful for traditionally difficult protein targets. This involves screening proteins for small inhibitor building blocks rather than larger drug-like molecules. Peripheral membrane proteins are particularly challenging proteins for inhibitor and drug development. We employ established fragment screening methods and develop new technologies to enable fragment-based drug design of membrane embedded proteins. The information gained form these screens is used in highly collaborative efforts in inhibitor development for the ultimate goal of obtaining chemical biology tools and drug leads.
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Graduate Students
Jake Breeden
Kelly Petersen
Neil Tiwari
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