Inflammation is a complex process with many lipid and peptide mediators involved. A large number of these mediators elicit either pro-inflammatory or pro-resolving effects through the action on G protein-coupled receptors (GPCRs). Our research is focused on a group of GPCRs as close phylogenetic neighbors, which comprises receptors for the pro-inflammatory mediators including anaphylatoxins, formylpeptides and prostaglandin D2 (PGD2), and the newly discovered specialized pro-resolving lipid mediators (SPMs) including lipoxin A4 (LXA4) and resolvins. The members of this GPCR family are active targets for developing new drugs for a variety of inflammatory diseases. So far no structures have been reported for this family. Thus our understanding of the molecular mechanisms underlying ligand action, receptor activation and signaling is quite limited, which has impeded drug development. To fill this knowledge gap, recently we have obtained crystal structures of two members in this family, the C5a receptor (C5aR) and the prostaglandin D2 receptor 2 (CRTH2). These two structures provided innovative information regarding the antagonism of C5aR and CRTH2. We propose to further define the molecular determinants for the diverse pharmacological action of C5aR and CRTH2 antagonists by testing novel hypotheses based our structures. We will take protein crystallography and electron microscopy (EM) approaches in parallel to obtain high-resolution structures of active C5aR and CRTH2 in complex with agonists and the Gi protein. The results will reveal the structural basis of agonist binding and receptor activation. In addition, we propose to develop small-molecule antagonists with new chemical scaffolds for C5aR and CRTH2 through structure-based drug design (SBDD) approach. We will also test the possibility of developing extracellular conformational antibodies of C5aR and CRTH2 as new pharmacological tools to block pro-inflammatory signaling pathways. The long-term goal is to move towards the clinical investigation of such new agents for C5aR and CRTH2. Another long-term research direction is to study GPCRs that mediate pro-resolving signaling pathways to promote inflammation resolution. FPR2/ALX (formylpeptide receptor 2/LXA4 receptor) will be our primary research target. FPR2/ALX can be targeted by a number of structurally unrelated mediators to mediate either pro-inflammatory or pro-resolving responses. Research on this receptor is aimed to reveal the structural basis for the action of diverse ligands and the molecular mechanism for the functional selectivity. Our study is significant for health because the discoveries will facilitate the development of innovative pharmacological tools for both anti-inflammatory and pro-resolving therapeutic strategies in the treatment of many inflammatory diseases.

Public Health Relevance

Our research is focused on a family of GPCRs in inflammation with the main focus on C5aR, CRTH2 and FPR2/ALX, which represent promising targets for developing new drugs for many inflammatory disorders. We take a variety of research strategies to elucidate the structural basis for receptor function and develop new agents targeting these receptors as novel pharmacological tools. The discoveries from our research will advance our understanding of inflammation biology and facilitate the development of new drugs for controlling inflammation in numerous diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
3R35GM128641-01S1
Application #
9891241
Study Section
Program Officer
Somers, Scott D
Project Start
2018-08-01
Project End
2023-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Wang, Lei; Yao, Dandan; Deepak, R N V Krishna et al. (2018) Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition. Mol Cell 72:48-59.e4