Physiology first and target identification later
In many disease contexts ––including cardiomyopathies, skeletal myopathies, vasospasm, bronchospasm, and cancer cell invasion–– cellular contractile force is a logical therapeutic target. To correctly hit that pathophysiological target, new drugs are often sought by means of unbiased high-throughput drug screens that focus upon molecular proxies for contractile force but are blind to contractile force itself. To overcome that limitation, and thus accelerate drug discovery, we present, Contractile Force Screening (CFS).
Drug screening using CFS
Human airway smooth muscle (ASM) cells were cultured to confluence upon Young’s modulus = 12 kPa (0.36% cross-linker) collagen-coated 96-well silicone substrates. (A–D) For a representative well of a 96-well plate, images of cells, fluorescent beads, traction force maps, and average magnitude (inset) at baseline are shown. (E and F) For the same well, shown are contraction maps and the average magnitude (inset) with the contractant compound histamine (10 μM, 30 min), and after additional treatment with the relaxant compound isoproterenol (0.5 μM, 30 min). (G) Over the 96-well plate, the force measurements are statistically different (p < 0.05) between positive and negative controls, as ascertained by an unpaired t-test. (H) Force measurements confirmed known differences in potency among a panel of functionally diverse ASM relaxation compounds (formoterol > salmeterol > salbutamol > isoproterenol). Plotted are the mean ± standard error calculated from three to eight wells per dose per ASM relaxation compound. Data were pooled from two to four 96-well plates tested on different days but under identical experimental conditions.
Yoshie et al, Biophys J
. 2018 May 8;114(9):2194-2199.
Statistics
Small
Set-up Cost
<1 week
Set-up time
Fast
Up to 1000 compounds per screening day
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