Structures and Interactions of Chemokine Receptors

Abstract
This is a revised competitive renewal application for a NIH R01 grant entitled “Structures and Interactions of
Chemokine Receptors” that has been continuously funded and very successful for 22 years. The long-
standing goals of this project are to understand the mechanisms of chemokines and their receptors in various
pathologies and to translate this information into the development of new intervention strategies. During the
past funding period, we have made significant progress toward these goals. Specifically, we have de novo
designed and chemically synthesized novel agonist molecules of CXCR4 receptor and completed a series of
studies to characterize their in vitro and in vivo biological activities in eliciting site-specific migration and
distribution of human neural stem cells and exerting significant and selective therapeutic effect in mice with
neurodegenerative disease. The molecular mechanisms of action of these agents have been analyzed with a
panel of point mutations at 24 residues located in each of the seven transmembrane domains of CXCR4 to
map critical sites for CXCR4-agonist recognition and signaling. To further advance these peptide agonists
toward potential therapeutics, we have developed a new strategy for peptide optimization with a small
molecule mimicry approach. A novel small molecule with potent biological activity in itself has been discovered
to mimic and to replace a large portion of the peptide agonist, resulting in a new prototype small molecule-
peptide conjugate agonist with much higher CXCR4 affinity, smaller size, and lower synthetic cost that are
advantageous for therapeutic development in the new grant period. These exciting discoveries and results
have laid a solid foundation for continuing translational research in regenerative medicine and basic research
to understand the mechanisms underlining stem cell migration and signaling.

Grant Number: 5R01GM057761-21
NIH Institute/Center: NIH
Principal Investigator: Jing An