A novel small molecule target in human airway smooth muscle for potential treatment of obstructive lung diseases

A staged high-throughput biophysical screening

Steven An, Peter S. Askovich, Thomas I. Zarembinski, Kwangmi Ahn, John M. Peltier, Moritz von Rechenberg, Sudhir Sahasrabudhe, Jeffrey J. Fredberg

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number8
JournalRespiratory Research
Volume12
DOIs
StatePublished - Jan 13 2011

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HSP20 Heat-Shock Proteins
14-3-3 Proteins
Obstructive Lung Diseases
Fluorescence Polarization
Smooth Muscle
Small Heat-Shock Proteins
Preclinical Drug Evaluations
Muscle Relaxation
Smooth Muscle Myocytes
Asthma
Costs and Cost Analysis
Therapeutics

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

A novel small molecule target in human airway smooth muscle for potential treatment of obstructive lung diseases : A staged high-throughput biophysical screening. / An, Steven; Askovich, Peter S.; Zarembinski, Thomas I.; Ahn, Kwangmi; Peltier, John M.; von Rechenberg, Moritz; Sahasrabudhe, Sudhir; Fredberg, Jeffrey J.

In: Respiratory Research, Vol. 12, 8, 13.01.2011.

Research output: Contribution to journalArticle

An, Steven ; Askovich, Peter S. ; Zarembinski, Thomas I. ; Ahn, Kwangmi ; Peltier, John M. ; von Rechenberg, Moritz ; Sahasrabudhe, Sudhir ; Fredberg, Jeffrey J. / A novel small molecule target in human airway smooth muscle for potential treatment of obstructive lung diseases : A staged high-throughput biophysical screening. In: Respiratory Research. 2011 ; Vol. 12.
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