Abstract

We will apply nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography to study enzymes from the methyl erythritol isoprenoid (MEP) biosynthetic pathway, which is essential in multiple pathogens and absent in humans. Identification and biophysical characterization of fragments which bind to MEP targets will generate data for the rational design of small molecule leads for MEP enzymatic inhibition. Through iterative synthesis and structure determination, we will develop these leads into novel compounds capable of binding MEP enzymes from a variety of infectious disease organisms. Success in this endeavor would lead to a Phase II proposal for focused synthesis and in vitro/in vivo potency testing to prove efficacy and advance these compounds closer to the clinic. The ultimate goal of this project is the development of novel treatments for those infected with drug-resistant strains of malaria, tuberculosis, and other microbial infections, as there are currently no MEP pathway inhibitor combination therapies approved for clinical usage

Public Health Relevance

This project proposes to utilize biophysical methods to discover lead compounds that bind to enzymes from the methyl erythritol isoprenoid (MEP) biosynthetic pathway. The ultimate goal of this project is the development of novel treatments for those infected with drug-resistant strains of malaria, tuberculosis, and other microbial infections, as there are currently no MEP pathway inhibitor combination therapies approved for clinical usage.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43AI093060-01
Application #
8058854
Study Section
Special Emphasis Panel (ZRG1-IMST-K (11))
Program Officer
Rogers, Martin J
Project Start
2010-12-01
Project End
2012-05-31
Budget Start
2010-12-01
Budget End
2012-05-31
Support Year
1
Fiscal Year
2011
Total Cost
$99,974
Indirect Cost

  Institution

Name
Emerald Biostructures
Department
Type
DUNS #
016974144
City
Bainbridge Island
State
WA
Country
United States
Zip Code
98110

  Publications

Zhang, Zheng; Jakkaraju, Sriram; Blain, Joy et al. (2013) Cytidine derivatives as IspF inhibitors of Burkolderia pseudomallei. Bioorg Med Chem Lett 23:6860-3
Begley, Darren W; Davies, Douglas R; Hartley, Robert C et al. (2011) Fragment screening of infectious disease targets in a structural genomics environment. Methods Enzymol 493:533-56
Begley, Darren W; Hartley, Robert C; Davies, Douglas R et al. (2011) Leveraging structure determination with fragment screening for infectious disease drug targets: MECP synthase from Burkholderia pseudomallei. J Struct Funct Genomics 12:63-76