학술논문
Selective Signal Capture from Multidimensional GPCR Outputs with Biased Agonists: Progress Towards Novel Drug Development.
Document Type
Academic Journal
Author
Kim D; Department of Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, 33612, USA.; Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, FL, 33612, USA.; Tokmakova A; Program in Biophysics, University of California, San Francisco, CA, 94102, USA.; Woo JA; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.; An SS; Rutgers Institute for Translational Medicine and Science, New Brunswick, NJ, 08901, USA.; Department of Pharmacology, Rutgers-Robert Wood Johnson Medical School, The State University of New Jersey, Piscataway, NJ, 08854, USA.; Goddard WA 3rd; Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA, 91125, USA.; Liggett SB; Department of Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, 33612, USA. sliggett@usf.edu.; Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, FL, 33612, USA. sliggett@usf.edu.; Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL, 33612, USA. sliggett@usf.edu.
Source
Publisher: Adis, Springer International Country of Publication: New Zealand NLM ID: 101264260 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1179-2000 (Electronic) Linking ISSN: 11771062 NLM ISO Abbreviation: Mol Diagn Ther Subsets: MEDLINE
Subject
Language
English
Abstract
G protein coupled receptors (GPCRs) are a superfamily of transmembrane-spanning receptors that are activated by multiple endogenous ligands and are the most common target for agonist or antagonist therapeutics across a broad spectrum of diseases. Initial characterization within the superfamily suggested that a receptor activated a single intracellular pathway, depending on the G protein to which it coupled. However, it has become apparent that a given receptor can activate multiple different pathways, some being therapeutically desirable, while others are neutral or promote deleterious signaling. The activation of pathways that limit effectiveness of a primary pathway or promote unwanted signals has led to abandonment of some GPCRs as drug targets. However, it is now recognized that the conformation of the receptor in its ligand-bound state can be altered by the structure of the agonist or antagonist to achieve pathway selectivity, a property termed biased signaling. Biased ligands could dramatically expand the number of novel drugs acting at GPCRs for new indications. However, the field struggles with the complexity and uncertainty of these structure-functions relationships. In this review we define the theoretical underpinnings of the biased effect, discuss the methods for measuring bias, and the pitfalls that can lead to incorrect assignments of bias. Using the recent elucidation of a β 2 -adrenergic receptor agonist that is biased in favor of Gs coupling over β-arrestin binding, we provide an example of how large libraries of compounds that are impartial to preconceived notions of agonist binding can be utilized to discover pathway-specific agonists. In this case, an agonist that lacks tachyphylaxis for the treatment of obstructive lung diseases was uncovered, with a structure that was distinctly different from other agonists. We show how biased characteristics were ascertained analytically, and how molecular modeling and simulations provide a structural basis for a restricted signaling repertoire.
(© 2022. The Author(s).)
(© 2022. The Author(s).)