My laboratory is interested in developing new and better ways to improve patient outcomes. We pursue a discovery-driven approach to find small molecules with improved function against known targets, and we create expressed sources of molecular diversity to identify and validate novel targets. We are currently evaluating and improving biased agonist candidates and allosteric modulators as part of a multidisciplinary program aimed at developing improved modalities for intervention in obstructive airway diseases. Bronchodilators that strongly bias towards canonical signaling should display enhanced efficacy while reducing tolerance and adverse events. Preliminary studies with biased agonists (pepducins) that promote non-canonical signaling support their utility not only for enhancing survival of heart tissue following ischemic insult but also for preserving cardiac contractility. Considering that suppression of cardiac contractility is one of the dose-limiting deficiencies of traditional beta-blockers, beta-agonists or allosteric modulators that bias towards non-canonical signaling may offer improvement over standard of care.
The recent structure of our Gs-biased allosteric modulator bound to the beta-2-adrenergic receptor suggests an entirely new approach to improve the pharmacologic activity of up to one third of all drugs. We are currently using this knowledge to design allosteric modulators that rescue the function of the beta-1-adrenergic receptor in heart failure.
Our recent discovery that acetylcholine-dependent smooth muscle contraction is largely calcium independent indicates that currently approved anti-muscarinic drugs have been mischaracterized for decades. We are now recharacterizing bronchoprotective drugs to prioritize use based on clinically relevant endpoints and developing new antimuscarinics that should offer greater clinical efficacy.
