G-protein coupled receptors (GPCRs) represent the single largest class of druggable targets in the human genome. Of the 390 or so druggable and non-olfactory human GPCRs there exist many which are orphan and/or understudied; we refer to these as ?oGPCRs?. Here we will illuminate the pharmacology, signaling pathways, chemical biology, distribution and function of the 143 oGPCRs listed in the RFA. This project seeks to discover and develop specific, community accessible tools? chemical probe molecules and engineered animals?that enable investigators to interrogate the biological functions of oGPCRs. Given the central importance of GPCRs for all areas of biomedical research, illuminating the pharmacology, function, signaling and chemical biology of these oGPCRs will have far-reaching impact for both therapeutics and basic biomedical science.

Public Health Relevance

G-protein coupled receptors respond to signals from light to adrenaline, lipids to chemokine proteins; GPCRs control physiology ranging from vision to respiration, heart rate to learning and memory and are the family of proteins most targeted by therapeutic drugs. Astonishingly, 1/3rd of the pharmacologically relevant GPCRs remain orphans, without specific reagents to control their activity. The advent of new technologies enables the development of chemical probes, genetic reporters and perturbants for the oGPCRs. This project will create novel tools suitable for illuminating the functions and ultimately public health relevance of oGPCRs that will enable new therapeutics for a wide variety of human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Resource-Related Research Projects--Cooperative Agreements (U24)
Project #
1U24DK116195-01
Application #
9451604
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Pawlyk, Aaron C
Project Start
2017-09-15
Project End
2023-08-31
Budget Start
2017-09-15
Budget End
2018-08-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Oprea, Tudor I; Bologa, Cristian G; Brunak, Søren et al. (2018) Unexplored therapeutic opportunities in the human genome. Nat Rev Drug Discov 17:317-332
McCorvy, John D; Butler, Kyle V; Kelly, Brendan et al. (2018) Structure-inspired design of ?-arrestin-biased ligands for aminergic GPCRs. Nat Chem Biol 14:126-134
Pera, Tonio; Deshpande, Deepak A; Ippolito, Michael et al. (2018) Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines. FASEB J 32:862-874
Wacker, Daniel; Stevens, Raymond C; Roth, Bryan L (2017) How Ligands Illuminate GPCR Molecular Pharmacology. Cell 170:414-427
Lansu, Katherine; Karpiak, Joel; Liu, Jing et al. (2017) In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat Chem Biol 13:529-536
Le Gonidec, Sophie; Chaves-Almagro, Carline; Bai, Yushi et al. (2017) Protamine is an antagonist of apelin receptor, and its activity is reversed by heparin. FASEB J 31:2507-2519
Roth, Bryan L; Irwin, John J; Shoichet, Brian K (2017) Discovery of new GPCR ligands to illuminate new biology. Nat Chem Biol 13:1143-1151
Butler, Kyle V; MacDonald, Ian A; Hathaway, Nathaniel A et al. (2017) Report and Application of a Tool Compound Data Set. J Chem Inf Model 57:2699-2706