This proposal "Molecular Mechanism of HIV Entry Mediated by Chemokine Receptor CCR5" is focused on X-ray structure determination of complexes between chemokine receptor CCR5, an HIV entry co- receptor, and a variety of ligands including peptidomimetics. The ultimate goal is to use the experimentally determined structure to carry out drug discovery aimed at inhibiting HIV cell entry using structure-based drug design (SBDD) approaches. CCR5 is the primary co-receptor responsible for HIV transmission, while emergence of CXCR4-tropic (X4-tropic) viruses later in infection correlates with a more rapid CD4 decline and a faster progression to AIDS. As the predominant co-receptor for HIV entry, CCR5 has long been taken as one of the most important drug targets. Five CCR5 targeted drugs to date have been brought to clinical trial, but only one, Maraviroc, has been approved by FDA. Molecular details of how this drug as well as other CCR5 cell entry inhibitors works are not understood and will be a focus of the proposed study. The proposed structural studies will be carried out using methods and approaches of the Gene-to-Structure-Pipeline that was developed by the GPCR Network.
The specific aims are: 1) Optimize the CCR5 construct design to generate large samples of highly purified and thermally stabilized CCR5 for biophysical and functional studies;2) Design and synthesize chemical tools that can be used to stabilize CCR5 and to probe ligand-receptor interactions;3) Develop an understanding of CCR5 ligand binding properties by determining the 3D structures of several complexes. It is expected that structural knowledge generated by our studies will lead to the development of new therapeutic strategies and help in stopping the growth of the HIV/AIDS epidemic in China and elsewhere in the world.

Public Health Relevance

The proposed project attempts to understand the ligand binding properties of the HIV co- receptor CCR5. Studies will then focus on using this knowledge to develop new therapeutic strategies against the virus with the expectation that this will help in combating the Global HIV/AIDS epidemic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI100604-03
Application #
8610241
Study Section
Special Emphasis Panel (ZRG1-IDM-R (50))
Program Officer
Sharma, Opendra K
Project Start
2012-02-15
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
$121,500
Indirect Cost
$9,000
Name
Shanghai Institute of Materia Medica
Department
Type
DUNS #
420985483
City
Shanghai
State
Country
China
Zip Code
Zhang, Kaihua; Zhang, Jin; Gao, Zhan-Guo et al. (2014) Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature 509:115-8
Zhang, Jin; Zhang, Kaihua; Gao, Zhan-Guo et al. (2014) Agonist-bound structure of the human P2Y12 receptor. Nature 509:119-22
Zhu, Lan; Zhao, Qiang; Wu, Beili (2013) Structure-based studies of chemokine receptors. Curr Opin Struct Biol 23:539-46
Tan, Qiuxiang; Zhu, Ya; Li, Jian et al. (2013) Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex. Science 341:1387-90