Abstract

This project will adapt the azide-alkyne cycloaddition reaction and related processes for use in the assembly of inhibitors of HIV protease, taking advantage of the dimeric structure of the enzyme, in two approaches. 1) Structures related to those possessing binding affinity for HIV protease will be functionalized with azide and alkyne groups. The assembly of these components into compounds with potential dual-site binding capability will be conducted in parallel combinatorial fashion both in the presence of the enzyme (the 'in situ' approach) and in standard combinatorial fashion. Both functional and alternative screens will be employed to identify leads, the latter employing new mass spectrometric techniques developed in our laboratories. (2) In-situ assembly will be used to rapidly develop inhibitors of protease mutants that have evolved to counter drug therapy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
2P01GM048870-11
Application #
6553756
Study Section
Special Emphasis Panel (ZRG1)
Project Start
1992-09-30
Project End
2007-08-31
Budget Start
Budget End
Support Year
11
Fiscal Year
2002
Total Cost
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; Ayeni, Christian; Breuer, Sebastian et al. (2010) Virtual screening for HIV protease inhibitors: a comparison of AutoDock 4 and Vina. PLoS One 5:e11955
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
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

Showing the most recent 10 out of 60 publications