DSM265: A Selective Plasmodium DHODH Inhibitor for Malaria Research
DSM265: A Selective Plasmodium DHODH Inhibitor for Malaria Research
DSM265 is a potent, selective small-molecule inhibitor of Plasmodium dihydroorotate dehydrogenase (DHODH) that blocks pyrimidine biosynthesis in malaria parasites and represents a promising tool compound for antimalarial drug discovery research.
- Target
- Plasmodium dihydroorotate dehydrogenase (DHODH)
- Pathway
- De novo pyrimidine biosynthesis
- Selectivity
- Selective for Plasmodium DHODH over human DHODH
- Parasite Species
- Active against Plasmodium falciparum and Plasmodium vivax
- CAS / SKU
- SKU: D656088 (Aladdin Scientific)
- Stage Activity
- Active against both blood-stage and liver-stage parasites
Mechanism of Action: Targeting Plasmodium DHODH
DSM265 exerts its antiparasitic activity by selectively inhibiting dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme that catalyzes the fourth step in the de novo biosynthesis of pyrimidines. Unlike mammalian cells, which can salvage pyrimidines from the bloodstream, Plasmodium parasites are entirely dependent on de novo pyrimidine synthesis for the production of nucleotides required for DNA and RNA replication. Inhibition of DHODH therefore halts parasite proliferation by depleting the pyrimidine pool essential for nucleic acid synthesis.
DSM265 binds to the ubiquinone-binding site on Plasmodium DHODH, blocking the electron transfer step that regenerates the enzyme's active form. Crucially, the compound exhibits high selectivity for the parasite enzyme over human DHODH, an important property that underpins its favorable therapeutic index and safety profile in preclinical models.
Selectivity Profile and Pharmacological Properties
A key advantage of DSM265 as a research tool is its high degree of selectivity for Plasmodium DHODH compared to the human ortholog. This selectivity arises from structural differences in the ubiquinone-binding pocket between the parasite and human enzymes, allowing DSM265 to potently inhibit the parasite enzyme while largely sparing the human enzyme. This selectivity profile reduces the likelihood of confounding cytotoxic effects when using DSM265 in cell-based assays.
Pharmacologically, DSM265 is characterized by favorable drug-like properties including good oral bioavailability and a long plasma half-life in preclinical species, making it suitable for both in vitro mechanistic studies and in vivo efficacy experiments in rodent malaria models. Researchers should note that precise IC50 values and pharmacokinetic parameters should be verified against the primary literature and the certificate of analysis supplied with each lot.
In Vitro and In Vivo Efficacy in Malaria Models
DSM265 has demonstrated potent activity against Plasmodium falciparum asexual blood-stage parasites in standard in vitro growth inhibition assays. Activity has also been reported against P. vivax and against liver-stage parasites, suggesting potential utility as a compound capable of targeting multiple life-cycle stages. The compound's activity against both asexual and early sexual stages makes it of particular interest to researchers studying transmission-blocking strategies.
In rodent malaria models using Plasmodium berghei or Plasmodium falciparum humanized mouse models, DSM265 has shown significant parasite suppression following oral dosing. These in vivo results, combined with its selectivity data, have supported its advancement into clinical evaluation. Researchers using DSM265 in animal studies should consult the primary literature for recommended dosing regimens and vehicle formulations, as these have not been independently verified by Aladdin Scientific.
Preparation, Handling, and Storage Recommendations
DSM265 (Aladdin Scientific SKU: D656088) is supplied as a solid powder. For stock solution preparation, DSM265 is typically dissolved in dimethyl sulfoxide (DMSO) to prepare concentrated stock solutions. Researchers should verify solubility limits and prepare fresh working dilutions in aqueous buffers or cell culture media immediately prior to use, minimizing DMSO concentration in final assay wells to avoid solvent-related cytotoxicity artefacts.
The compound should be stored at the temperature specified on the product label and certificate of analysis, protected from light and moisture. Repeated freeze-thaw cycles should be avoided to maintain compound integrity. Aliquoting stock solutions upon first thaw is strongly recommended. Always consult the supplied safety data sheet (SDS) before handling, and follow institutional guidelines for the safe disposal of chemical waste.
Ordering DSM265 from Aladdin Scientific
Aladdin Scientific supplies DSM265 (SKU: D656088) to support malaria research, parasitology, and drug discovery programs worldwide. Each lot is accompanied by a certificate of analysis confirming identity, purity, and physical characteristics. For bulk quantities, custom packaging, or technical inquiries, please contact our scientific support team.
To place an order or obtain a quotation, visit the product page on the Aladdin Scientific website or contact your regional sales representative. Aladdin Scientific is committed to providing high-quality research reagents with reliable documentation to support reproducible science.
Frequently asked questions
What is the primary molecular target of DSM265?
DSM265 selectively targets Plasmodium dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme essential for de novo pyrimidine biosynthesis in malaria parasites. By inhibiting this enzyme, DSM265 depletes the pyrimidine nucleotide pool required for parasite DNA and RNA synthesis, halting proliferation.
How selective is DSM265 for Plasmodium DHODH versus human DHODH?
DSM265 exhibits high selectivity for the Plasmodium DHODH enzyme over the human ortholog. This selectivity is attributed to structural differences in the enzyme's ubiquinone-binding pocket between the parasite and human forms. Researchers should consult the primary literature for quantitative selectivity ratios, as specific values should be verified against published data.
Which Plasmodium species and life-cycle stages does DSM265 inhibit?
DSM265 has demonstrated activity against Plasmodium falciparum and Plasmodium vivax. It is active against asexual blood-stage parasites and has also shown activity against liver-stage parasites, making it a valuable tool for studying multiple points of intervention in the malaria parasite life cycle.
How should DSM265 be dissolved for in vitro assays?
DSM265 is typically dissolved in DMSO to prepare a concentrated stock solution. Working dilutions should be prepared in the appropriate aqueous assay buffer or cell culture medium immediately before use. The final DMSO concentration in assay wells should be minimized and kept consistent across all treatment and control groups to avoid solvent-mediated artefacts.
What is the Aladdin Scientific SKU for DSM265?
DSM265 is available from Aladdin Scientific under SKU D656088. For pricing, availability, and technical documentation including the certificate of analysis and safety data sheet, please visit the product page or contact our sales team.
References
- Phillips MA et al. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci Transl Med. 2015.
- Coteron JM et al. Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J Med Chem. 2011.
- Llanos-Cuentas A et al. A Phase 2, randomized, single-blind, placebo-controlled dose-escalation trial to assess the efficacy and safety of DSM265 in patients with Plasmodium falciparum or Plasmodium vivax malaria. Lancet Infect Dis. 2018.
Products are supplied for research and development use only. Not for use in humans, animals, diagnosis, or therapy.
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