Chemistry Seminar with Dr. Brian Fuglestad from Virginia Commonwealth University at 4:00pm

Abstract: Despite comprising over 10% of the human proteome, peripheral membrane proteins (PMPs) have been insufficiently investigated. Defined by reversible membrane-binding, their functionally relevant membrane-adhered state is particularly mysterious for many proteins of this type. Their function in the communication between the cellular membrane and the cytosol or other aqueous compartments makes PMPs essential targets for further molecular study. Additionally, the central role of many PMPs in biological and disease-related processes makes PMPs attractive, yet elusive, drug targets. Our goals are to illuminate their functional mechanisms, use this information to target them for small-molecule inhibition, while developing new tools and methods for enhanced PMP studies. A fragment-based approach has proved successful for p47phox, an essential activator of the NADPH oxidase enzyme, which has proven to be a difficult drug target for inflammatory and other diseases. This suggests that membrane-anchoring PMPs of this type may in fact be druggable using the right approaches. For some other PMP types, preventing the membrane-anchoring activation event is less feasible as an inhibition strategy. An example is glutathione peroxidase 4 (GPx4), a lipid-processing enzyme that is a high-profile target for cancer treatment. Screening for small-molecule binding of this membrane-embedded enzyme necessitated development of a fragment-screening-tolerant membrane model, which we call membrane mimicking reverse micelles (mmRMs). The mmRM system allowed discovery of non-covalent small-molecules that we are developing into GPx4 inhibitors. The mmRM system not only allows entry points for fragment-based drug discovery for difficult targets, but also enhances biophysical and structural studies of membrane-bound PMPs. These examples, and others, highlight the importance of applying and developing new technologies to PMPs to better understand them on a molecular level and to leverage this information for therapeutic lead development.

Hosted by Prof Yusuke Okuno