Journal article
Chemo-Immunotherapeutic Antimalarials Targeting Isoprenoid Biosynthesis
ACS medicinal chemistry letters, Vol.4(4), pp.423-427
04/11/2013
DOI: 10.1021/ml4000436
PMCID: PMC3630516
PMID: 23610597
Abstract
We synthesized 30 lipophilic bisphosphonates
and tested them in
malaria parasite killing (targeting parasite geranylgeranyl diphosphate
synthase, GGPPS) and human γδ T cell activation (targeting
human farnesyl diphosphate synthase, FPPS). Similar patterns of activity
were seen in inhibiting human FPPS and
Plasmodium
GGPPS, with short to medium chain-length species having most activity.
In cells, shorter chain-length species had low activity, due to poor
membrane permeability, and longer chain length species were poor enzyme
inhibitors. Optimal activity was thus seen with ∼C
10
side-chains, which have the best combination of enzyme inhibition
and cell penetration. We also solved the crystal structure of one
potent inhibitor, bound to FPPS. The results are of interest since
they suggest the possibility of a combined chemo/immuno-therapeutic
approach to antimalarial development in which both direct parasite
killing and γδ T cell activation can be achieved with
a single compound.
Details
- Title: Subtitle
- Chemo-Immunotherapeutic Antimalarials Targeting Isoprenoid Biosynthesis
- Creators
- Yonghui Zhang - , Zhangjiagang 215600, People’s Republic of ChinaWei Zhu - Department of ChemistryYi-Liang Liu - Department of ChemistryHong Wang - Division of Immunology, Department of Internal Medicine, the Interdisciplinary Graduate Program in ImmunologyKe Wang - Department of ChemistryKai Li - Department of ChemistryJoo Hwan No - Center for Neglected Diseases Drug DiscoveryLawrence Ayong - Center for Neglected Diseases Drug DiscoveryAnmol Gulati - Department of ChemistryRan Pang - Department of ChemistryLucio Freitas-Junior - Center for Neglected Diseases Drug DiscoveryCraig T Morita - Division of Immunology, Department of Internal Medicine, the Interdisciplinary Graduate Program in ImmunologyEric Oldfield - Department of Chemistry
- Resource Type
- Journal article
- Publication Details
- ACS medicinal chemistry letters, Vol.4(4), pp.423-427
- Publisher
- American Chemical Society
- DOI
- 10.1021/ml4000436
- PMID
- 23610597
- PMCID
- PMC3630516
- ISSN
- 1948-5875
- eISSN
- 1948-5875
- Language
- English
- Date published
- 04/11/2013
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984094748702771
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