DSM265: Mechanism, Applications & Key Research FAQs

DSM265 is a potent and highly selective inhibitor of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), representing a promising clinical-stage antimalarial compound that targets the parasite's de novo pyrimidine biosynthesis pathway.

Target

Plasmodium dihydroorotate dehydrogenase (DHODH)

Primary Indication

Malaria (Plasmodium falciparum and P. vivax)

Mechanism

Selective inhibition of parasite DHODH, blocking de novo pyrimidine synthesis essential for parasite survival

Selectivity

Highly selective for Plasmodium DHODH over human DHODH

Product SKU

D656088

Research Stage

Clinical-stage investigational antimalarial compound

What Is DSM265 and How Does It Work?

DSM265 is a triazolopyrimidine-based small molecule developed as a selective inhibitor of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), a mitochondrial enzyme that is essential for the de novo biosynthesis of pyrimidines in malaria parasites. Unlike human cells, which can salvage preformed pyrimidines from the bloodstream, Plasmodium parasites rely exclusively on de novo synthesis, making DHODH an attractive and validated drug target.

By binding to a species-specific hydrophobic pocket on PfDHODH, DSM265 competitively blocks the enzyme's activity, thereby starving the parasite of the pyrimidine nucleotides required for DNA and RNA synthesis. This ultimately halts parasite replication and leads to parasite death. The compound demonstrates activity against both blood-stage and liver-stage parasites, broadening its potential utility in malaria prevention and treatment.

What Is the Selectivity Profile of DSM265?

A critical advantage of DSM265 is its high selectivity for Plasmodium DHODH over the human ortholog (HsDHODH). This selectivity arises from structural differences in the inhibitor-binding site between the parasite and human enzymes. The species-selective binding minimizes the risk of on-target toxicity to human cells, which is a major consideration in antimalarial drug development.

DSM265 has been shown to inhibit both P. falciparum and P. vivax DHODH, providing potential coverage against the two most clinically significant Plasmodium species responsible for human malaria. Researchers should note that selectivity data should always be confirmed under the specific assay conditions used in their laboratory.

How Is DSM265 Used in Research Applications?

DSM265 is used in a variety of preclinical research contexts related to antimalarial drug discovery and parasitology:

• In vitro parasite culture assays: DSM265 is employed to assess antiparasitic potency against P. falciparum strains in erythrocyte culture systems, providing IC₅₀ data for comparative studies.
• Enzyme inhibition assays: Researchers use DSM265 as a tool compound and positive control in PfDHODH biochemical assays to validate hits from screening campaigns.
• Liver-stage models: The compound's activity against hepatic-stage parasites makes it a useful probe in liver-stage infection models.
• Resistance mechanism studies: DSM265 is used to investigate resistance emergence and DHODH mutation profiles, contributing to understanding of antimalarial resistance mechanisms.

All research applications should be conducted under appropriate biosafety conditions and in compliance with institutional regulations governing work with infectious agents.

Handling, Storage, and Solubility Considerations

Proper handling and storage of DSM265 are essential to maintain compound integrity and ensure reproducible experimental results. The following general guidelines apply; researchers should always consult the specific Certificate of Analysis (CoA) provided with each lot:

• Storage: Store DSM265 as a solid at low temperature (typically −20 °C), protected from light and moisture, in a tightly sealed container.
• Solubility: DSM265 exhibits limited aqueous solubility. It is generally soluble in organic solvents such as DMSO. Prepare stock solutions in DMSO and dilute into aqueous buffers or cell culture media immediately before use, keeping final DMSO concentrations below levels that may affect cell viability or assay performance (typically ≤0.1%).
• Stability: Avoid repeated freeze-thaw cycles. Aliquot stock solutions upon first use to preserve compound integrity.
• Safety: Handle DSM265 according to standard laboratory safety practices for research-use-only chemical compounds. Refer to the Safety Data Sheet (SDS) for full hazard information.

How to Order DSM265 from Aladdin Scientific

DSM265 (SKU: D656088) is available from Aladdin Scientific for research use. To place an order or request additional product information:

• Search for SKU D656088 on the Aladdin Scientific website to access current pricing, available pack sizes, and stock status.
• Bulk quantities and custom packaging may be available upon request; contact our technical sales team for a quote.
• A Certificate of Analysis (CoA) and Safety Data Sheet (SDS) are available for download on the product page or by contacting customer support.
• For technical questions regarding the suitability of DSM265 for a specific application, our scientific support team is available to assist.

All products are intended for research use only and are not suitable for human therapeutic, diagnostic, or veterinary applications.

Frequently asked questions

What is the primary biological target of DSM265?

The primary target of DSM265 is Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), a mitochondrial enzyme essential for de novo pyrimidine biosynthesis in malaria parasites. Inhibition of this enzyme deprives the parasite of nucleotides needed for replication.

Is DSM265 selective for Plasmodium DHODH over human DHODH?

Yes, DSM265 is designed to be highly selective for Plasmodium DHODH relative to the human ortholog, exploiting structural differences in the enzyme's inhibitor-binding site between the parasite and human enzymes. This selectivity is intended to minimize potential on-target toxicity in human cells.

What Plasmodium species does DSM265 show activity against?

DSM265 has demonstrated inhibitory activity against both Plasmodium falciparum and Plasmodium vivax DHODH, the two most clinically important species causing human malaria. Researchers should verify activity profiles under their specific experimental conditions.

In which solvents is DSM265 soluble, and how should stock solutions be prepared?

DSM265 has limited aqueous solubility and is generally soluble in DMSO. Stock solutions should be prepared in DMSO at an appropriate concentration, aliquoted to avoid freeze-thaw cycles, and diluted into aqueous media immediately prior to use. Final DMSO concentrations in assays should be kept minimal, typically at or below 0.1%, to avoid solvent-related artifacts.

Can DSM265 be used as a positive control in DHODH enzyme assays?

Yes, DSM265 is well-established in the literature as a selective PfDHODH inhibitor and is commonly used as a positive control or reference compound in DHODH biochemical and cellular assays. Confirm lot-specific purity and activity data from the Certificate of Analysis before use.

How should DSM265 be stored to maintain stability?

DSM265 should be stored as a solid at −20 °C, protected from light and moisture in a tightly sealed container. Prepared DMSO stock solutions should be aliquoted and stored at −20 °C, and repeated freeze-thaw cycles should be avoided to preserve compound integrity.

References

1. Phillips MA et al. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Science Translational Medicine, 2015.
2. Llanos-Cuentas A et al. Clinical candidate DSM265 is a potent inhibitor of Plasmodium falciparum and Plasmodium vivax dihydroorotate dehydrogenase. Antimicrobial Agents and Chemotherapy, 2018.

Products are supplied for research and development use only. Not for use in humans, animals, diagnosis, or therapy.