Abstract |
Trimethoprim, an antifolate commonly prescribed in combination with sulfamethoxazole, potently inhibits several prokaryotic species of dihydrofolate reductase (DHFR). However, several eukaryotic pathogenic organisms are resistant to trimethoprim, preventing its effective use as a therapeutic for those infections. We have been building a program to reengineer trimethoprim to more potently and selectively inhibit eukaryotic species of DHFR as a viable strategy for new drug discovery targeting several opportunistic pathogens. We have developed a series of compounds that exhibit potent and selective inhibition of DHFR from the parasitic protozoa Cryptosporidium and Toxoplasma as well as the fungus Candida glabrata. A comparison of the structures of DHFR from the fungal species Candida glabrata and Pneumocystis suggests that the compounds may also potently inhibit Pneumocystis DHFR.
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Authors | Jieying Liu, David B Bolstad, Erin S D Bolstad, Dennis L Wright, Amy C Anderson |
Journal | Eukaryotic cell
(Eukaryot Cell)
Vol. 8
Issue 4
Pg. 483-6
(Apr 2009)
ISSN: 1535-9786 [Electronic] United States |
PMID | 19168759
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Folic Acid Antagonists
- Fungal Proteins
- Protozoan Proteins
- Trimethoprim
- Tetrahydrofolate Dehydrogenase
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Topics |
- Amino Acid Sequence
- Animals
- Candida glabrata
(chemistry, enzymology)
- Drug Design
- Folic Acid Antagonists
(chemistry, pharmacology)
- Fungal Proteins
(antagonists & inhibitors, chemistry, metabolism)
- Humans
- Molecular Sequence Data
- Opportunistic Infections
(drug therapy, microbiology, parasitology)
- Pneumocystis
(chemistry, enzymology)
- Protozoan Proteins
(antagonists & inhibitors, chemistry, metabolism)
- Sequence Alignment
- Structure-Activity Relationship
- Tetrahydrofolate Dehydrogenase
(chemistry, metabolism)
- Toxoplasma
(chemistry, enzymology)
- Trimethoprim
(chemistry, pharmacology)
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