Abstract

This project is directed to the development of small-molecule and peptidomimetic inhibitors for blocking Bacillus anthracis (anthrax), Yersinia pestis (plague), Variola major (smallpox and other pox viruses), and Clostridium botulinum, by targeting their respective toxins: LF and PA, YopH, CrmA, BoNT/C. In close collaboration with Projects Cores, we will use a combination of virtual and high-throughput screening and novel synthetic approaches guided by NMR-based drug design strategies for generating small-molecule and peptidomimetic inhibitors. Given the arsenal of techniques proposed in this project, we anticipate being able within the course of the program to identify and characterize high affinity inhibitors for most of the targeted toxins.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI055789-03
Application #
7250828
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$806,345
Indirect Cost

  Institution

Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Aleshin, Alexander E; DiScipio, Richard G; Stec, Boguslaw et al. (2012) Crystal structure of C5b-6 suggests structural basis for priming assembly of the membrane attack complex. J Biol Chem 287:19642-52
Shiryaev, Sergey A; Chernov, Andrei V; Shiryaeva, Tatiana N et al. (2011) The acidic sequence of the NS4A cofactor regulates ATP hydrolysis by the HCV NS3 helicase. Arch Virol 156:313-8
Stranzl, Gudrun R; Santelli, Eugenio; Bankston, Laurie A et al. (2011) Structural insights into inhibition of Bacillus anthracis sporulation by a novel class of non-heme globin sensor domains. J Biol Chem 286:8448-58
Low, Lieh Yoon; Yang, Chen; Perego, Marta et al. (2011) Role of net charge on catalytic domain and influence of cell wall binding domain on bactericidal activity, specificity, and host range of phage lysins. J Biol Chem 286:34391-403
Zhai, Dayong; Yu, Eric; Jin, Chaofang et al. (2010) Vaccinia virus protein F1L is a caspase-9 inhibitor. J Biol Chem 285:5569-80
Zhao, Li-Chun; Yang, Bo; Wang, Rengang et al. (2010) Type C botulinum toxin causes degeneration of motoneurons in vivo. Neuroreport 21:14-18
Shiryaev, Sergey A; Radichev, Ilian A; Ratnikov, Boris I et al. (2010) Isolation and characterization of selective and potent human Fab inhibitors directed to the active-site region of the two-component NS2B-NS3 proteinase of West Nile virus. Biochem J 427:369-76
Remacle, Albert G; Gawlik, Katarzyna; Golubkov, Vladislav S et al. (2010) Selective and potent furin inhibitors protect cells from anthrax without significant toxicity. Int J Biochem Cell Biol 42:987-95
Chan, Siew Leong; Mukasa, Takashi; Santelli, Eugenio et al. (2010) The crystal structure of a TIR domain from Arabidopsis thaliana reveals a conserved helical region unique to plants. Protein Sci 19:155-61
Shiryaev, Sergey A; Strongin, Alex Y (2010) Structural and functional parameters of the flaviviral protease: a promising antiviral drug target. Future Virol 5:593-606

Showing the most recent 10 out of 48 publications