ArticlePLoS neglected tropical diseases2016
Trypanosoma brucei DHFR-TS Revisited: Characterisation of a Bifunctional and Highly Unstable Recombinant Dihydrofolate Reductase-Thymidylate Synthase.
Article in PLoS neglected tropical diseases, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 32 citations in OpenAlex.
- Identification of Innovative Folate Inhibitors Leveraging the Amino Dihydrotriazine Motif from Cycloguanil for Their Potential as Anti-ACS infectious diseases · 2024Article
- Hybrid Caffeic Acid-Based DHFR Inhibitors as Novel Antimicrobial and Anticancer Agents.Antibiotics (Basel, Switzerland) · 2024Article
- In Silico and In Vitro Search for Dual Inhibitors of theMolecules (Basel, Switzerland) · 2023Article
- Preliminary Structure-Activity Relationship Study of the MMV Pathogen Box Compound MMV675968 (2,4-Diaminoquinazoline) Unveils Novel Inhibitors ofMolecules (Basel, Switzerland) · 2022Article
- Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1.Journal of medicinal chemistry · 2022Article
- Sesquiterpene Lactones with Dual Inhibitory Activity against theMolecules (Basel, Switzerland) · 2021Article
- Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Dual and selective inhibitors of pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHFR-TS) fromJournal of enzyme inhibition and medicinal chemistry · 2019Article
- Article
- Development of Chemical Proteomics for the Folateome and Analysis of the Kinetoplastid Folateome.ACS infectious diseases · 2018Article
- Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To InhibitACS omega · 2017Article
- Lausannevirus Encodes a Functional Dihydrofolate Reductase Susceptible to Proguanil.Antimicrobial agents and chemotherapy · 2017Article
- Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need.Nature reviews. Microbiology · 2017Review
- The Role of Folate Transport in Antifolate Drug Action in Trypanosoma brucei.The Journal of biological chemistry · 2016Article
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5 authors at 1 institution in 1 country.
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Abstract
Bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) is a chemically and genetically validated target in African trypanosomes, causative agents of sleeping sickness in humans and nagana in cattle. Here we report the kinetic properties and sensitivity of recombinant enzyme to a range of lipophilic and classical antifolate drugs. The purified recombinant enzyme, expressed as a fusion protein with elongation factor Ts (Tsf) in ThyA- Escherichia coli, retains DHFR activity, but lacks any TS activity. TS activity was found to be extremely unstable (half-life of 28 s) following desalting of clarified bacterial lysates to remove small molecules. Stability could be improved 700-fold by inclusion of dUMP, but not by other pyrimidine or purine (deoxy)-nucleosides or nucleotides. Inclusion of dUMP during purification proved insufficient to prevent inactivation during the purification procedure. Methotrexate and trimetrexate were the most potent inhibitors of DHFR (Ki 0.1 and 0.6 nM, respectively) and FdUMP and nolatrexed of TS (Ki 14 and 39 nM, respectively). All inhibitors showed a marked drop-off in potency of 100- to 1,000-fold against trypanosomes grown in low folate medium lacking thymidine. The most potent inhibitors possessed a terminal glutamate moiety suggesting that transport or subsequent retention by polyglutamylation was important for biological activity. Supplementation of culture medium with folate markedly antagonised the potency of these folate-like inhibitors, as did thymidine in the case of the TS inhibitors raltitrexed and pemetrexed.
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