This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. HIV-1 protease and HCV NS3 protease are both enzymes that are required for HIV and HCV infection respectably. Therefore these enzymes are considered ideal targets for anti-viral drugs for the treatment of these diseases. For HIV there are currently 9 protease inhibitors available and several HCV NS3 protease inhibitors are currently in clinical trials. Unfortunately drug-resistance to most of these inhibitors has been observed in replicon studies and/or treated patent populations. Our lab views drug-resistance as a change in molecular recognition such that the target enzyme retains the ability to cleave viral substrates but is no longer able to bind inhibitor. In many HIV-1 protease variants multiple site mutations co-evolve to both decrease the affinity of a particular inhibitor and increase the viability and fitness of the enzyme. Crystallographic studies of HIV-1 protease and HCV NS3 protease in complex with substrates and inhibitors will prove to be valuable in order to determine molecular interactions that mediate substrate recognition while decreasing affinity to a particular inhibitor. Structural insights gained by analyzing high resolution crystal structures of HIV-1 protease and HCV NS3 protease in complex with substrates and inhibitors will serve as a guide to develop high affinity inhibitors that are more robust against emerging drug resistant in both viral systems.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR007707-19
Application #
8363697
Study Section
Special Emphasis Panel (ZRG1-BCMB-P (40))
Project Start
2011-08-01
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
19
Fiscal Year
2011
Total Cost
$21,623
Indirect Cost
Name
University of Chicago
Department
Miscellaneous
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Kazantsev, Roman V; Dannenhoffer, Adam J; Weingarten, Adam S et al. (2017) Crystal-Phase Transitions and Photocatalysis in Supramolecular Scaffolds. J Am Chem Soc 139:6120-6127
Fournier, Bertrand; Sokolow, Jesse; Coppens, Philip (2016) Analysis of multicrystal pump-probe data sets. II. Scaling of ratio data sets. Acta Crystallogr A Found Adv 72:250-60
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Sampath, Sujatha; Yarger, Jeffery L (2015) Structural hysteresis in dragline spider silks induced by supercontraction: An x-ray fiber micro-diffraction study. RSC Adv 5:1462-1473
Coppens, Philip; Fournier, Bertrand (2015) New methods in time-resolved Laue pump-probe crystallography at synchrotron sources. J Synchrotron Radiat 22:280-7

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