HIV-1 encodes 15 different proteins, yet current drug therapies target only 2 of these 15 proteins (HIV Protease and Reverse Transcriptase). Targeting additional HIV-1 proteins is an important strategy in the continuing battle against AIDS.
Three Specific Aims proposed in this project are 1) Discover peptides, through a combinatorial phage-display approach, which bind with high affinity to the HIV-1 Vpu protein; 2) Determine the high resolution NMR structure of one or more of the Vpu-binding peptides; 3) Determine the NMR structure of the corresponding peptide binding site on Vpu with bound peptide. Phage display will allow rapid screening of many millions of different peptides to identify those which bind Vpu tightly, and which may be antagonists of Vpu-protein interactions which occur in HIV-infected cells. The structure of high-affinity Vpu-binding peptide(s), as fusion proteins with the bacteriophage pVIII protein, will be determined using NMR methods pioneered in the Opella laboratory. The structure of the non-transmembrane portion of Vpu (Vpu 28-81), with bound high-affinity peptide, will be determined using solution NMR methods. This may provide valuable information to direct the rational design of a new class of Vpu-targeting, anti-HIV drugs. Importantly, the methods developed during this project will also be widely applicable to drug discovery research involving many other diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM063300-02
Application #
6526119
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Whitmarsh, John
Project Start
2001-08-01
Project End
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
2
Fiscal Year
2002
Total Cost
$38,320
Indirect Cost
Name
University of California San Diego
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Thiriot, David S; Nevzorov, Alexander A; Opella, Stanley J (2005) Structural basis of the temperature transition of Pf1 bacteriophage. Protein Sci 14:1064-70
Thiriot, David S; Nevzorov, Alexander A; Zagyanskiy, Lena et al. (2004) Structure of the coat protein in Pf1 bacteriophage determined by solid-state NMR spectroscopy. J Mol Biol 341:869-79
Mesleh, Michael F; Lee, Sangwon; Veglia, Gianluigi et al. (2003) Dipolar waves map the structure and topology of helices in membrane proteins. J Am Chem Soc 125:8928-35