tailieunhanh - Báo cáo y học: " A novel small molecule target in human airway smooth muscle for potential treatment of obstructive lung diseases: a staged highthroughput biophysical screening"

Tuyển tập các báo cáo nghiên cứu về y học được đăng trên tạp chí y học 'Respiratory Research cung cấp cho các bạn kiến thức về ngành y đề tài:" A novel small molecule target in human airway smooth muscle for potential treatment of obstructive lung diseases: a staged highthroughput biophysical screening. | An et al. Respiratory Research 2011 12 8 http content 12 1 8 RESPIRATORY RESEARCH RESEARCH Open Access A novel small molecule target in human airway smooth muscle for potential treatment of obstructive lung diseases a staged high-throughput biophysical screening 1 t 2t 2 3 2 Steven S An Peter S Askovich Thomas I Zarembinski Kwangmi Ahn John M Peltier Moritz von Rechenberg2 Sudhir Sahasrabudhe2 Jeffrey J Fredberg4 Abstract Background A newly identified mechanism of smooth muscle relaxation is the interaction between the small heat shock protein 20 HSP20 and 14-3-3 proteins. Focusing upon this class of interactions we describe here a novel drug target screening approach for treating airflow obstruction in asthma. Methods Using a high-throughput fluorescence polarization FP assay we screened a library of compounds that could act as small molecule modulators of HSP20 signals. We then applied two quantitative cell-based biophysical methods to assess the functional efficacy of these molecules and rank-ordered their abilities to relax isolated human airway smooth muscle ASM . Scaling up to the level of an intact tissue we confirmed in a concentration-responsive manner the potency of the cell-based hit compounds. Results Among 58 019 compound tested 268 compounds caused 20 or more reduction of the polarized emission in the FP assay. A small subset of these primary screen hits belonging to two scaffolds caused relaxation of isolated ASM cell in vitro and attenuated active force development of intact tissue ex vivo. Conclusions This staged biophysical screening paradigm provides proof-of-principle for high-throughput and cost-effective discovery of new small molecule therapeutic agents for obstructive lung diseases. Background For treatment of bronchospasm in asthma a well known target is the p2-adrenergic receptor p2-AR on smooth muscle that wraps circumferentially around the conducting airways 1 . By triggering relaxation of this airway smooth .