The objective of this research is to use a combination of EPR, ENDOR, NMR, X-ray crystallographic, synthetic and computational methods to investigate the structure, function, and inhibition of isoprenoid biosynthesis enzymes of interest as drug targets for treating, primarily, tropical diseases.
In Aim 1, we will investigate GcpE, an enzyme involved in isoprenoid biosynthesis in malaria parasites. We hypothesize that its mechanism of action involves unusual metallacycles and that similar metallacycles form with novel alkyne inhibitors. GcpE is an excellent target for the development of novel anti-infectives since it is essential for pathogen survival, is not found in humans, and we have now identified novel inhibitors.
In Aim 2 we will carry out a similar series of investigations of the following enzyme (from P. falciparum) in the pathway, LytB, and we hypothesize that because of similarities in their mechanism of action, LytB inhibitors will also inhibit GcpE leading, in cells, to synergistic activity.
The third Aim i s to develop novel anti-malarials that function by blocking carotenoid and quinone biosynthesis. Carotenoids act to remove reactive oxygen species (ROS, from hemoglobin catabolism) and we hypothesize that carotenoid (and quinone) biosynthesis inhibitors will synergize with current anti-malarials (that enhance ROS formation), reducing drug resistance.
The final Aim i nvolves investigation of three other high-value targets: in trypanosomatid parasites, farnesyl diphosphate synthase and hexokinase, in bacteria, undecaprenyl diphosphate synthase. All are essential for survival and sub-micromolar leads have already been identified by us. If successful, the work will provide many new insights into enzyme mechanisms, as well as new drug leads for many global infectious diseases.

Public Health Relevance

This project is aimed at developing new leads for treating infectious diseases, primarily malaria. Focus will be on developing inhibitors for three unique targets in malaria parasites, and on the use of novel drugs against sleeping sickness.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM065307-12
Application #
8532682
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Anderson, Vernon
Project Start
2002-06-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
12
Fiscal Year
2013
Total Cost
$335,294
Indirect Cost
$110,787
Name
University of Illinois Urbana-Champaign
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Kim, Meekyum Olivia; Feng, Xinxin; Feixas, Ferran et al. (2015) A Molecular Dynamics Investigation of Mycobacterium tuberculosis Prenyl Synthases: Conformational Flexibility and Implications for Computer-aided Drug Discovery. Chem Biol Drug Des 85:756-69
Han, Xu; Chen, Chun-Chi; Kuo, Chih-Jung et al. (2015) Crystal structures of ligand-bound octaprenyl pyrophosphate synthase from Escherichia coli reveal the catalytic and chain-length determining mechanisms. Proteins 83:37-45
Sinko, William; Wang, Yang; Zhu, Wei et al. (2014) Undecaprenyl diphosphate synthase inhibitors: antibacterial drug leads. J Med Chem 57:5693-701
Guerra, Francisco; Wang, Ke; Li, Jikun et al. (2014) Inhibition of the 4Fe-4S Proteins IspG and IspH: an EPR, ENDOR and HYSCORE Investigation. Chem Sci 5:1642-1649
Li, Kai; Schurig-Briccio, Lici A; Feng, Xinxin et al. (2014) Multitarget drug discovery for tuberculosis and other infectious diseases. J Med Chem 57:3126-39
Wang, Weixue; Oldfield, Eric (2014) Bioorganometallic chemistry with IspG and IspH: structure, function, and inhibition of the [Fe(4)S(4)] proteins involved in isoprenoid biosynthesis. Angew Chem Int Ed Engl 53:4294-310
Liu, Wenting; Feng, Xinxin; Zheng, Yingying et al. (2014) Structure, function and inhibition of ent-kaurene synthase from Bradyrhizobium japonicum. Sci Rep 4:6214
Benaim, Gustavo; Casanova, Paola; Hernandez-Rodriguez, Vanessa et al. (2014) Dronedarone, an amiodarone analog with improved anti-Leishmania mexicana efficacy. Antimicrob Agents Chemother 58:2295-303
Oldfield, Eric; Feng, Xinxin (2014) Resistance-resistant antibiotics. Trends Pharmacol Sci 35:664-74
Chan, Hsiu-Chien; Feng, Xinxin; Ko, Tzu-Ping et al. (2014) Structure and inhibition of tuberculosinol synthase and decaprenyl diphosphate synthase from Mycobacterium tuberculosis. J Am Chem Soc 136:2892-6

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