This is a competitive renewal application for a NIH RO1 grant entitled "Structures and Interactions of Chemokine Receptors" that has been continuously funded and very successful for more than 13 years. The long-standing interest and goals in this project are to understand the structure-function relationship and mechanism of chemokines and their receptors in various pathologies and to translate such information into the development of new intervention strategies. During the past funding period, we have made significant progress towards these goals. Specifically, as described in the Progress Report, using the strategy of "Synthetically and Modularly Modified Chemokines (SMM-chemokines)" developed by us previously, we have designed and synthesized a novel agonist molecule of CXCR4 receptor and completed a series of studies to characterize the in vitro and in vivo biological activities of this de novo CXCR4 agonist in activating and directing neural stem cell migration. As CXCR4 plays a critical role in the migration of neural stem cells during tissue repairs, our novel CXCR4 agonist molecule has opened new possibilities for studying the mechanism of targeted human neural stem cell migration mediated by chemokine ligands and receptors and developing new therapeutics for tissue repairs. In this renewal application, we propose to apply this exciting discovery to the development of new analogs of this novel CXCR4 agonist with optimized pharmacological and biological properties as tools to further probe the structure-function relationship and mechanism of CXCR4-ligand binding and signaling and drug leads to develop new medicines for promoting stem cell-based tissue repairs. The underlying hypothesis is that de novo synthetic ligands of CXCR4, created by chemically conjugating the two molecular moieties mimicking the essential binding and signaling functions of natural chemokine ligands of CXCR4, can be novel synthetic chimera serving as new molecular probes and drug candidates.

Public Health Relevance

This is a competitive renewal application for a NIH RO1 grant entitled Structures and Interactions of Chemokine Receptors that has been continuously funded and very successful for more than 13 years. The long-standing interest and goals in this project are to understand the structure-function relationship and mechanism of chemokines and their receptors in various pathologies and to translate such information into the development of new intervention strategies. During the past funding period, we have made significant progress towards these goals. Specifically, as described in the Progress Report, using the strategy of Synthetically and Modularly Modified Chemokines (SMM-chemokines) developed by us previously, we have designed and synthesized a novel agonist molecule of CXCR4 receptor and completed a series of studies to characterize the in vitro and in vivo biological activities of this de novo CXCR4 agonist in activating and directing neural stem cell migration. As CXCR4 plays a critical role in the migration of neural stem cells during tissue repairs, our novel CXCR4 agonist molecule has opened new possibilities for studying the mechanism of targeted human neural stem cell migration mediated by chemokine ligands and receptors and developing new therapeutics for tissue repairs. In this renewal application, we propose to apply this exciting discovery to the development of new analogs of this novel CXCR4 agonist with optimized pharmacological and biological properties as tools to further probe the structure-function relationship and mechanism of CXCR4-ligand binding and signaling and drug leads to develop new medicines for promoting stem cell-based tissue repairs. The underlying hypothesis is that de novo synthetic ligands of CXCR4, created by chemically conjugating the two molecular moieties mimicking the essential binding and signaling functions of natural chemokine ligands of CXCR4, can be novel synthetic chimera serving as new molecular probes and drug candidates.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01GM057761-14A1
Application #
8632631
Study Section
(DDNS)
Program Officer
Fabian, Miles
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Yang, Yilei; Zhang, Qinghao; Gao, Mei et al. (2014) A novel CXCR4-selective high-affinity fluorescent probe and its application in competitive binding assays. Biochemistry 53:4881-3
Choi, Won-Tak; Yang, Yilei; Xu, Yan et al. (2014) Targeting chemokine receptor CXCR4 for treatment of HIV-1 infection, tumor progression, and metastasis. Curr Top Med Chem 14:1574-89
Xu, Yan; Duggineni, Srinivas; Espitia, Stephen et al. (2013) A synthetic bivalent ligand of CXCR4 inhibits HIV infection. Biochem Biophys Res Commun 435:646-50
Dong, Chang-Zhi; Tian, Shaomin; Choi, Won-Tak et al. (2012) Critical role in CXCR4 signaling and internalization of the polypeptide main chain in the amino terminus of SDF-1α probed by novel N-methylated synthetically and modularly modified chemokine analogues. Biochemistry 51:5951-7
Choi, Won-Tak; Duggineni, Srinivas; Xu, Yan et al. (2012) Drug discovery research targeting the CXC chemokine receptor 4 (CXCR4). J Med Chem 55:977-94
Choi, Won-Tak; Kumar, Santhosh; Madani, Navid et al. (2012) A novel synthetic bivalent ligand to probe chemokine receptor CXCR4 dimerization and inhibit HIV-1 entry. Biochemistry 51:7078-86
Kawatkar, Sameer P; Yan, Maocai; Gevariya, Harsukh et al. (2011) Computational analysis of the structural mechanism of inhibition of chemokine receptor CXCR4 by small molecule antagonists. Exp Biol Med (Maywood) 236:844-50
Choi, Won-Tak; An, Jing (2011) Biology and clinical relevance of chemokines and chemokine receptors CXCR4 and CCR5 in human diseases. Exp Biol Med (Maywood) 236:637-47
Li, Ying; Liu, Dongxiang; Cao, Rong et al. (2007) Crystal structure of chemically synthesized vMIP-II. Proteins 67:243-6
Choi, Won-Tak; Kaul, Marcus; Kumar, Santosh et al. (2007) Neuronal apoptotic signaling pathways probed and intervened by synthetically and modularly modified (SMM) chemokines. J Biol Chem 282:7154-63

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