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Targeting DHFR in parasitic protozoa.
1Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA. Amy.C.Anderson@Dartmouth.edu
Drug Discovery Today
|February 19, 2005
Summary
Apicomplexan parasites cause severe global diseases like malaria. New dihydrofolate reductase-thymidylate synthase (DHFR-TS) inhibitors are being developed to combat drug resistance and treat diseases like cryptosporidiosis.
Area of Science:
- Parasitology
- Drug Discovery
- Biochemistry
Background:
- Apicomplexan parasites cause significant global health issues, including malaria, toxoplasmosis, and cryptosporidiosis.
- The enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) is essential for pyrimidine biosynthesis in these parasites.
- Existing DHFR inhibitors are effective for toxoplasmosis and malaria but face challenges with resistance and lack of treatment for cryptosporidiosis.
Purpose of the Study:
- To develop novel inhibitors targeting DHFR-TS in parasitic apicomplexans.
- To address the growing problem of drug resistance in malaria parasites.
- To find effective therapies for cryptosporidiosis.
Main Methods:
- Utilizing recently determined crystal structures of parasitic DHFR-TS enzymes.
- Structure-based drug design of novel DHFR inhibitors.
- In vitro and in vivo testing of inhibitor efficacy and resistance profiles.
Main Results:
- Identification of novel DHFR inhibitor candidates.
- Demonstration of potential efficacy against drug-resistant malaria strains.
- Exploration of therapeutic avenues for cryptosporidiosis.
Conclusions:
- Novel DHFR inhibitors designed using structural information show promise.
- These inhibitors could overcome existing drug resistance mechanisms.
- Further development is needed to establish effective therapies for apicomplexan infections, particularly cryptosporidiosis.