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 #
5R01GM065307-11
Application #
8324616
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
2012-09-01
Budget End
2013-08-31
Support Year
11
Fiscal Year
2012
Total Cost
$347,455
Indirect Cost
$114,805
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
Liu, Meixia; Chen, Chun-Chi; Chen, Lu et al. (2016) Structure and Function of a ""Head-to-Middle"" Prenyltransferase: Lavandulyl Diphosphate Synthase. Angew Chem Int Ed Engl 55:4721-4
Rao, Guodong; Oldfield, Eric (2016) Structure and Function of Four Classes of the 4Fe-4S Protein, IspH. Biochemistry 55:4119-29
Desai, Janish; Wang, Yang; Wang, Ke et al. (2016) Isoprenoid Biosynthesis Inhibitors Targeting Bacterial Cell Growth. ChemMedChem 11:2205-2215
Wang, Yang; Desai, Janish; Zhang, Yonghui et al. (2016) Bacterial Cell Growth Inhibitors Targeting Undecaprenyl Diphosphate Synthase and Undecaprenyl Diphosphate Phosphatase. ChemMedChem 11:2311-2319
Li, Jikun; Feng, Xinxin; Zhu, Wei et al. (2016) Chemical Exchange Saturation Transfer (CEST) Agents: Quantum Chemistry and MRI. Chemistry 22:264-71
Zhang, Lilan; Chen, Chun-Chi; Ko, Tzu-Ping et al. (2016) Moenomycin Biosynthesis: Structure and Mechanism of Action of the Prenyltransferase MoeN5. Angew Chem Int Ed Engl 55:4716-20
García-García, Verónica; Oldfield, Eric; Benaim, Gustavo (2016) Inhibition of Leishmania mexicana Growth by the Tuberculosis Drug SQ109. Antimicrob Agents Chemother 60:6386-9
Desai, Janish; Liu, Yi-Liang; Wei, Hongli et al. (2016) Structure, Function, and Inhibition of Staphylococcus aureus Heptaprenyl Diphosphate Synthase. ChemMedChem 11:1915-23
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
Yang, Gyongseon; Zhu, Wei; Wang, Yang et al. (2015) In Vitro and in Vivo Activity of Multitarget Inhibitors against Trypanosoma brucei. ACS Infect Dis 1:388-98

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