Friday, September 13, 2024
9/13/2024
PROJECT SUMMARY/ABSTRACT In a 2007 editorial in NEJM, we proposed that depleting airway smooth muscle of myosin – the contractile mo- tor protein responsible for myocyte contraction – would be an effective strategy for preventing acute asthma attacks, but no drug strategy to accomplish this was available. However, a clever new class of compounds, Proteolysis Targeting Chimeras (PROTACs), has been developed that could achieve this goal. These small, bifunctional molecules catalyze proteasome degradation of a targeted protein by stimulating its ubiquitination. Each PROTAC contains one moiety that binds to the targeted protein, and is connected through a linker to a second “bait” moiety that binds an E3 ligase; when both sides are bound, the E3 ligase is brought close to the targeted protein, which it ubiquitinates and so targets for degradation. The process is catalytic because the PROTAC is released upon target degradation and is available for another cycle of target binding, E3 ligase re- cruitment, and target ubiquitination. Here, we propose to test the new idea that a PROTAC to degrade smooth muscle myosin within airway smooth muscle cells could be used as a new treatment for asthma. Smooth muscle myosin has a long half-life and slow turnover rate and so seems ideally suited for degradation by PROTACs. Depleting airway myocytes of myosin would drastically impair contraction, and PROTACs targeting smooth muscle myosin (SMM-PROTACs) should prevent acute airway constriction in eve- ryone with asthma. In this R21 proposal, we will pursue proof-of-principle experiments aimed at demonstrating SMM-PROTACs can inhibit bronchoconstriction, through the execution of four specific aims: 1) Synthesize and characterize a small series of prototype SMM-PROTACs 2) Demonstrate that SMM-PROTACs degrade smooth muscle myosin in human airway smooth muscle, but do not degrade cardiac, skeletal, or non-muscle myosins 3) Demonstrate that SMM-PROTACs inhibit constriction of airways in human lung slices 4) Demonstrate that SMM-PROTACs delivered into the airways blunt methacholine (MCh)-induced bron- choconstriction in mice Demonstration that SMM-PROTACs can inhibit bronchoconstriction by selectively stimulating degradation of smooth muscle myosin would justify their further preclinical development as a novel asthma treatment. This finding would also justify evaluation of whether SMM-PROTACs inhibit progression of other diseases in which smooth muscle contraction plays a key role.
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