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.

Agonists of the beta-2-adrenergic receptor (B2AR) are critical bronchodilators in management of obstructive airway diseases, but many commonly used bronchodilators were developed before mechanisms for receptor desensitization, non-canonical signaling, recycling and degradation were elucidated. Although these drugs have improved quality of life for millions of patients, chronic use of bronchodilators (especially long-acting agonists) can increase the risk of fatal asthmatic attacks, which is why these drugs carry a black box warning. Mounting evidence suggests that non-canonical signaling, which is downstream of receptor desensitization, may play a role in the etiology of adverse events. My laboratory has discovered allosteric effectors that promote canonical signaling and suppress receptor desensitization. Bronchodilators that strongly bias towards canonical signaling should display enhanced efficacy while reducing tolerance and adverse events. 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.

As hearts fail, adrenal glands increase production of catecholamines (epinephrine, norepinephrine) to compensate for reduced cardiac output. Unfortunately, the resulting mechanical and metabolic stress accelerates heart damage, which is why drugs that counteract catecholamine stimulation (beta-blockers) are standard therapy for heart failure. While most of these drugs compete with catecholamines for receptor binding without promoting increased heart rate or contractile force (antagonists), biased agonists that promote GRK and arrestin-mediated receptor desensitization and internalization while suppressing canonical signaling offer an alternative mechanism for beta-blocking activity that has the dual advantages of sequestering the receptor from catecholamine stimulation and promoting non-canonical signaling, which is cardioprotective. 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 (Grisanti, et al., Theranostics (2018)), but, unexpectedly, also for preserving cardiac contractility (Carr, et al., PNAS (2016)). 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.