Abstract
Pharmacological chaperoning by small compounds that stabilize and increase the steady-state intracellular levels of functional conformations of disease-causing protein variants is a relatively novel therapeutic approach. Customary screens are based on the monitoring of protein stabilization, where differential scanning fluorimetry is a method that has been successfully used to discover initial hits, notably for soluble cytoplasmic proteins. High-throughput biophysical screens of recombinantly expressed integral membrane proteins solubilized in detergent are less common. We here present DSF-based screens for either soluble or membrane proteins, using SYPRO Orange and N-[4-(7-diethylamino-4-methyl-3-coumarinyl)phenyl]maleimide (CPM) as the fluorescent dyes, respectively. Furthermore, concentration-dependent DSF is also an adequate method for first validation of initial hits for further characterization and initiation of hit-to-lead chemistry programs for the development of drug candidates to treat misfolding genetic diseases.
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