Applications of Biomembranes in Drug Discovery
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Applications of Biomembranes in Drug Discovery Ye Fang, Yulong Hong, Brian Webb, and Joydeep Lahiri Abstract Molecules in the cell membrane are key targets for therapeutic intervention. Technologies that enable the preservation of membrane-bound targets in their biomimetic and pharmacologically active states for screening of potential drug compounds are of great interest to bio-pharmaceutical companies. This review discusses emerging biomembrane technologies with a focus on biomembrane microarrays that enable the parallel analysis of multiple membrane-bound targets. Keywords: biological, biomedical, biomimetic, cellular.
Introduction In addition to providing a semipermeable barrier, the cell membrane is the start site for highly regulated, vectorial signaling events through which the cell communicates with its environment.1,2 Molecules associated with the cell membrane— lipids, proteins, and small molecules—are not only the recognition sites for exogenous signals, but also are often directly involved in downstream signal transduction through dynamic interactions with intracellular proteins. Nearly every aspect of cellular physiology is impacted by these signaling events. The modulation of membrane-bound molecules is a major mechanism for modern therapeutic intervention. More than 50% of current drug targets are membrane-bound; membrane proteins such as G protein-coupled receptors (GPCRs), ion channels, and receptor tyrosine kinases have been some of the most successful drug targets. GPCRs alone account for approximately half of current drug targets, with more than $23.5 billion in annual pharmaceutical sales ascribed to medications that address this target class.3–5 Drugs typically function by selectively modulating the function of an intended target (e.g., by blocking the binding of its native ligand). In general, the appropriateness of a target for therapeutic intervention
MRS BULLETIN • VOLUME 31 • JULY 2006
is determined by many factors, including its differential expression between normal and disease populations, its network of interaction(s) with other targets, its location and mechanism for regulation, and its physiological and pathological roles in model organism-based and disease-based systems. Whole-cell-based approaches are popular for studying the function and dynamic targeting of molecules to membrane-bound targets. However, because of the complexity of cellular networks6 and interactions,7,8 and the unique cellular context for any given type of cell,9 the ability to unambiguously ascertain target-compound binding and affinity is often compromised. Direct measurements using the purified protein are typically not viable because the structural and pharmacological fidelity of these targets is dependent on a host membrane; therefore, technologies that preserve or reconstitute the target–membrane host structure are valuable. Membranes on solid supports, so-called supported membranes,10 offer this potential and have already proven invaluable in addressing fundamental questions about the physical and chemi
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