Abstract

We will use X-ray crystallography to study the molecular structure of the Feline Immunodeficiency Virus protease (FIV PR) as the basis for a program aimed at developing the tools for structure and mechanism based drug design. Understanding of the molecular structure of the FIV PR in that context will contribute to the development of AIDS therapeutics based on inhibiting the HIV-1 PR. First, the molecular structure of FIV PR will be worked out by modelling based on the structures of RSV PR and HIV-1 PR determined in our laboratory. Such a model will be useful in experimentally determining the X-ray crystallographic structure of the FIV PR, and for preliminary inhibitor design. The crystal structure of FIV PR will be determined, unliganded and as a complex with substrate-based inhibitors. This information will be used in an initial round of inhibitor/drug design. Inhibitors selected from this first round of design will be used in further studies of the FIV PR-inhibitor complex. Selected PR-inhibitor complexes will be determined to very high resolution to provide the basis for quantitative understanding of enzyme-ligand interactions. Refined inhibitor design and improvement of the design tools will be based on data obtained in this iterative fashion. The FIV PR structures obtained will be compared and contrasted with the RSV PR and HIV-1 PR structures to draw general inferences concerning the structural origins of the properties of these important retroviral enzymes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM048870-09
Application #
6340974
Study Section
Project Start
2000-09-01
Project End
2001-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
9
Fiscal Year
2000
Total Cost
$113,837
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Morris, Garrett M; Green, Luke G; Radi?, Zoran et al. (2013) Automated docking with protein flexibility in the design of femtomolar ""click chemistry"" inhibitors of acetylcholinesterase. J Chem Inf Model 53:898-906
Breuer, Sebastian; Sepulveda, Homero; Chen, Yu et al. (2011) A cleavage enzyme-cytometric bead array provides biochemical profiling of resistance mutations in HIV-1 Gag and protease. Biochemistry 50:4371-81
Chang, Max W; Torbett, Bruce E (2011) Accessory mutations maintain stability in drug-resistant HIV-1 protease. J Mol Biol 410:756-60
Chang, Max W; Giffin, Michael J; Muller, Rolf et al. (2010) Identification of broad-based HIV-1 protease inhibitors from combinatorial libraries. Biochem J 429:527-32
Chang, Max W; Ayeni, Christian; Breuer, Sebastian et al. (2010) Virtual screening for HIV protease inhibitors: a comparison of AutoDock 4 and Vina. PLoS One 5:e11955
Sundstrom, Magnus; Chatterji, Udayan; Schaffer, Lana et al. (2008) Feline immunodeficiency virus OrfA alters gene expression of splicing factors and proteasome-ubiquitination proteins. Virology 371:394-404
Nelson, Josh D; Kinkead, Heather; Brunel, Florence M et al. (2008) Antibody elicited against the gp41 N-heptad repeat (NHR) coiled-coil can neutralize HIV-1 with modest potency but non-neutralizing antibodies also bind to NHR mimetics. Virology 377:170-83
Giffin, Michael J; Heaslet, Holly; Brik, Ashraf et al. (2008) A copper(I)-catalyzed 1,2,3-triazole azide-alkyne click compound is a potent inhibitor of a multidrug-resistant HIV-1 protease variant. J Med Chem 51:6263-70
Huey, Ruth; Morris, Garrett M; Olson, Arthur J et al. (2007) A semiempirical free energy force field with charge-based desolvation. J Comput Chem 28:1145-52
Heaslet, Holly; Rosenfeld, Robin; Giffin, Mike et al. (2007) Conformational flexibility in the flap domains of ligand-free HIV protease. Acta Crystallogr D Biol Crystallogr 63:866-75

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