The prevalence of drug-resistance in infectious diseases such as malaria demands efforts to identify new anti-infective agents. Targeting essential isoprenoid biosynthetic enzymes is a potential strategy for the development of new antimalarial agents. This application is focused on the invention of a chemical strategy to permit cellular uptake and efficient intracellular activation of two polar inhibitor classes targeting the late stage MEP pathway enzyme, IspG, and farnesylpyrophosphate synthase (FPPS). FPPS is potently inhibited by the clinically-used anti-osteoporosis agent, zoledronate, and emerging evidence suggests zoledronate exerts antiparasitic and antibacterial effects in vitro. However, the polyanionic nature of this bisphosphonate at physiologic pH prevents efficient cellular uptake into extraskeletal cells at clinically achievable serum concentrations. Similar challenges will exit in achieving high intracellular concentrations of linear diphosphate analogs designed to act as potent mechanism-based inhibitors of MEP pathway enzyme IspG, or other MEP pathway enzymes in which polyphosphorylated groups are essential components for inhibitor binding and recognition. This application proposes a novel chemical strategy to overcome these critical barriers. The proposed studies will develop prodrug activation chemistry employing minimal bioactivation steps to unmask multiple negative charges, within parasites. We will implement this strategy to dramatically enhance the antimalarial properties of FPPS-targeting zoledronate (Aim 1) and linear diphosphates targeting IspG (Aim 2). These studies will provide a foundation for the transformation of highly polar, potent inhibitors of isoprenoid biosynthesis into useful therapeutic agents for the treatment of infectious diseases.

Public Health Relevance

Targeting essential isoprenoid biosynthetic enzymes is a promising avenue for the development of new antimalarial agents. Currently, potent inhibitors of pathogen isoprenoid biosynthesis are not therapeutically useful due to poor cellular uptake. The proposed studies will develop a novel chemical strategy to enhance cell permeability of negatively charged diphosphate analogs known to act on isoprenoid biosynthetic enzymes farnesylpyrophosphate synthase and the nonmevalonate biosynthetic enzyme, IspG.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI099704-02
Application #
8416422
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Rogers, Martin J
Project Start
2012-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$202,500
Indirect Cost
$77,500
Name
Johns Hopkins University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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