DSM265 / Medicines for Malaria Venture - LARVOL DELTA

Inner-mitochondrial membrane protein PfMPV17 is linked to P. falciparum in vitro resistance to the indoloquinolizidine alkaloid alstonine. (PubMed, J Antimicrob Chemother) - "These data demonstrate that PfMPV17 is linked to alstonine resistance and suggest that alstonine action is linked to the mitochondria and/or pyrimidine biosynthesis pathways."

Journal • Preclinical • Infectious Disease • Malaria

Progress and Prospects of Triazoles in Advanced Therapies for Parasitic Diseases. (PubMed, Trop Med Infect Dis) - "Preclinical studies in models of Chagas disease, leishmaniasis, malaria, and helminth infections demonstrate that derivatives like posaconazole, ravuconazole, and DSM265 exhibit potent in vitro and in vivo activity, although their primarily static effects have limited their success as monotherapies in chronic cases. Despite challenges in achieving complete parasite clearance and managing potential toxicity, interdisciplinary efforts across medicinal chemistry, parasitology, and clinical research highlight the significant potential of triazoles as components of next-generation, patient-friendly antiparasitic regimens. These findings support the further optimization and clinical evaluation of triazole-based agents to improve treatments for neglected parasitic diseases."

Journal • Review • Infectious Disease • Malaria

Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention. (PubMed, J Med Chem) - "The lead compound DSM1465 is more potent and has improved absorption, distribution, metabolism and excretion/pharmacokinetic (ADME/PK) properties compared to DSM265 that support the potential for once-monthly chemoprevention at a low dose. This compound meets the objective of identifying compounds with potential to be used for monthly chemoprevention in Africa to support malaria elimination efforts."

Journal • Infectious Disease • Malaria

Minimum Inoculum of Resistance Studies to Support Antimalarial Drug Discovery (ASTMH 2024) - "Here, we present our MIR studies on five different targets: dihydroorotate dehydrogenase (PfDHODH), ATPase4 (PfATP4), translation elongation factor 2 (PfeEF2), acetyl CoA synthetase (PfACS), and phosphatidylinositol-4 kinase (PfPI4K), targeted by the compounds DSM265, KAE609, M5717, MMV019721 and MMV390048, respectively. Data from these results can be used to predict whether resistance would be quickly selected in the field. Compounds with robust MIR data can be used as a positive control for studies to assess the resistance liabilities of candidate therapeutics."

Infectious Disease • Malaria

Recent advances, challenges and updates on the development of therapeutics for malaria. (PubMed, EXCLI J) - "This review is primarily concerned with the description of newly synthesized antimalarial compounds, i.e. Tafenoquine, Cipargamin, Ferroquine, Artefenomel, DSM265, MMV390048 designed to improve the activity of pure antimalarial enantiomers. In this review, we selected the representative malarial drugs in clinical trials, classified them with detailed targets according to their action, discussed the relationship within the human trials, and generated a summative discussion with prospective expectations."

Journal • Review • Infectious Disease • Malaria

A comprehensive review of synthetic strategies and SAR studies for the discovery of PfDHODH inhibitors as antimalarial agents. Part 1: triazolopyrimidine, isoxazolopyrimidine and pyrrole-based (DSM) compounds. (PubMed, Bioorg Chem) - "Among them, triazolopyrimidines, isoxazolopyrimidines, and pyrrole-based derivatives known as DSM compounds showed tremendous potential as novel antimalarial agents, and one of the triazolopyrimidine-based compounds (DSM265) was able to reach phase IIa clinical trials...We have also summarized SAR study of all these PfDHODH inhibitors. In an attempt to assist readers, scientists, and researchers involved in the development of new PfDHODH inhibitors as antimalarials, this review provides accessibility of all synthetic techniques and SAR studies of the most promising triazolopyrimidines, isoxazolopyrimidines, and pyrrole-based PfDHODH inhibitors."

Journal • Review • Infectious Disease • Malaria

Diverse evolutionary pathways challenge the use of collateral sensitivity as a strategy to suppress resistance. (PubMed, Elife) - "We focus on one compound, TCMDC-125334, which was active against all mutant lines tested, including the DHODH C276Y line, which arose in selections with the clinical candidate DSM265...This selected for parasites with a DHODH V532A mutation which were cross-resistant to both compounds and were as fit as the wildtype parent in vitro. The emergence of these cross-resistant, evolutionarily fit parasites highlights the mutational flexibility of the DHODH enzyme."

Journal • Infectious Disease • Malaria

Pentafluorosulfanyl: an atypical functional group with high impact in the development of a clinical candidate for Malaria (ACS-Fall 2023) - "Optimisation efforts of the triazolopyrimidine-based series led to the identification of DSM265 as a clinical candidate. This comunication will describe in detail the medicinal chemistry programme undertaken and the impact of the introduction of the pentafluorosulfanyl functional group in the identification and development of DSM265."

Clinical • Infectious Disease • Malaria

Microfluidic synthesis of multilayered lipid–polymer hybrid nanoparticles for the formulation of low solubility drugs (ACS-Fall 2023) - "In this study, we present a microfluidics-based approach to produce lipid nanoparticles (LNPs) for the manufacturing of multilayered hybrid nanoparticles (HNPs). Using X-ray scattering, cryo-electron microscopy, and polarized microscopy, we demonstrate that the hybrid membranes consisting of phosphatidylcholine (PC) and PBD-b-PEO (poly(butadiene-block-ethylene oxide)) can be transformed into dense and multilayered HNPs, which are ideal for carrying low-solubility drugs of the Biopharmaceutical Classification System (BCS) II and IV such as antimalarial DSM265 and Paclitaxel, respectively."

Infectious Disease

Microfluidic synthesis of multilayered lipid-polymer hybrid nanoparticles for the formulation of low solubility drugs. (PubMed, Soft Matter) - "Here, we report on the development of a microfluidics-based strategy analogous to produce lipid nanoparticles (LNPs) for the nanomanufacturing of multilayered hybrid nanoparticles (HNPs). Using X-ray scattering, Cryo-electron, and polarized microscopy we show that phosphatidylcholine (PC) and PBD-b-PEO (poly(butadiene-block-ethylene oxide)) hybrid membranes can be nanomanufactured by microfluidics into HNPs with dense and multilayered cores which are ideal carriers of low-solubility drugs of the Biopharmaceutical Classification System (BCS) II and IV such as antimalarial DSM265 and Paclitaxel, respectively."

Journal • Infectious Disease

A pharmacokinetic-pharmacodynamic model for chemoprotective agents against malaria. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "There are either concerns about unacceptable adverse effects such as neuropsychiatric sequalae (mefloquine), risks of hemolysis in patients with G6PD deficiency (8-aminoquinolines such as tafenoquine), or cost and daily dosing (atovaquone-proguanil)...Here we present a pharmacokinetic-pharmacodynamic (PKPD) model constructed using DSM265 (a dihydroorotate dehydrogenase inhibitor with activity against the liver schizonts of malaria, therefore, a prophylaxis candidate)...Furthermore, by integrating clinical data, the killing effect of the drug on liver- and blood-stage parasites can be included in the PKPD model, and a clinical outcome can be predicted. Despite multiple challenges, the presented model has the potential to help translation from preclinical to late development for new chemoprophylactic candidates."

Journal • PK/PD data • CNS Disorders • Hematological Disorders • Infectious Disease • Malaria • Metabolic Disorders • Psychiatry • Schizophrenia

Susceptibility of Plasmodium falciparum isolates from eastern Uganda to antimalarial compounds under development (ASTMH 2022) - "In general, field isolates were highly susceptible, with median IC50s in the low nM range for compounds targeting PfCYTb (ELQ300, 13 nM); PfDHODH (DSM265, 3.6 nM; DSM421, 20 nM; DSM632, 9.8 nM; DSM705, 11 nM; DSM1049, 22 nM; BRD1331 13 nM), PfEF2 (DDD498, 0.6 nM); PfPheRS (BRD5018, 1.6 nM); and PfPI4K (MMV048, 60 nM; UCT943, 11 nM). Three mutations (N957H, I876V and Y883H) in PfPI4K were associated with slightly decreased susceptibility to MMV048 (median IC50 WT vs mutant: 55 nM vs 74 nM for N957H, 61 nM vs 75 nM for I876V, and 60 nM vs 77 nM for Y883H). Overall, Ugandan P. falciparum isolates were highly susceptible to 11 compounds under development as next-generation antimalarials, consistent with a lack of pre-existing or novel resistance-conferring mutations in circulating Ugandan parasites."

Infectious Disease • Malaria

Development of a biomarker to monitor target engagement after treatment with dihydroorotate dehydrogenase inhibitors. (PubMed, Biochem Pharmacol) - "Treatment of mice with leflunomide (teriflunomide prodrug) caused a large dose-dependent build-up of DHO in blood (up to 16-fold) and urine (up to 5,400-fold) that was not observed for mice treated with DSM265. Thus, any toxicity associated with DSM265 treatment in mice is likely caused by off-target mechanisms. The identification of a robust biomarker for mammalian DHODH inhibition represents an important advance to generally monitor for on-target effects in preclinical and clinical applications of DHODH inhibitors used to treat human disease."

Biomarker • Journal • Infectious Disease • Malaria

An Overview on Synthetic and Medicinal Perspectives of [1,2,4]Triazolo[1,5-a]pyrimidine Scaffold. (PubMed, Chem Biodivers) - "Several clinical trials and marketed drugs such as Trapidil, Essramycin, Pyroxsulam, DSM-265, Flumetsulam, GNF-6702, and Cevipabulin indicate the potential of [1,2,4]triazolo[1,5-a]pyrimidine moiety with various functional groups in medicinal chemistry. Herein, we represent a concise report focusing on the synthetic strategies used for diversely substituted [1,2,4]triazolo[1,5-a]pyrimidine analogs and their pharmacological applications. To the best of our knowledge, since 1980, we are the first to write a review on this emerging scaffold, which reveals the synthetic strategies, and pharmacological activities of differently substituted [1,2,4]triazolo[1,5-a]pyrimidine with special emphasis on structure-activity relationship studies."

Journal • Review • Oncology

Remarkably coherent population structure for a dominant Antarctic Chlorobium species. (PubMed, Microbiome) - "The factors shaping Antarctic microbial communities are gradually being defined. In addition to the cold, the annual variation in sunlight hours dictates which phototrophic species can grow and the extent to which they contribute to ecosystem processes. The Chlorobium population studied was inferred to provide cobalamin, in addition to carbon, nitrogen, hydrogen, and sulphur cycling, as critical ecosystem services. The specific Antarctic environmental factors and major ecosystem benefits afforded by this GSB likely explain why such a coherent population structure has developed in this Chlorobium species. Video abstract."

Clinical • Journal

Ex vivo susceptibility to new antimalarial agents differs among human-infecting Plasmodium species. (PubMed, Int J Parasitol Drugs Drug Resist) - "Several promising antimalarial drugs are currently being tested in human trials, such as artefenomel, cipargamin, ferroquine and ganaplacide...However, using our in vitro adapted line, we demonstrated recently that P. knowlesi is significantly less susceptible than P. falciparum to some new antimalarial drugs (e.g., cipargamin and DSM265), and more susceptible to others (e.g., ganaplacide)...Our findings highlight the need to ensure cross species susceptibility profiles are determined early in the drug development pipeline. Our data can also be used to inform further drug development, and illustrate the utility of the P. knowlesi in vitro model as a scalable approach for predicting the drug susceptibility of non-falciparum malaria species in general."

Journal • Preclinical • Infectious Disease • Malaria

Identification of 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase. (PubMed, Int J Mol Sci) - "PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue...Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development."

Journal • Infectious Disease • Malaria

Seeking an optimal dosing regimen for OZ439/DSM265 combination therapy for treating uncomplicated falciparum malaria. (PubMed, J Antimicrob Chemother) - "Our results show that the combination of OZ439 and DSM265 can be a promising alternative to replace ACTs. Our model can be used to inform future Phase 2 and 3 clinical trials of OZ439/DSM265, fast-tracking the deployment of this combination therapy in the regions where ACTs are failing. The dosing regimens that are shown to be efficacious and within safe and tolerable limits are suggested for future investigations."

Combination therapy • Journal • Infectious Disease • Malaria

Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series. (PubMed, J Med Chem) - "Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa...Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes."

Journal • CNS Disorders • Infectious Disease • Malaria • Psychiatry • Schizophrenia

Lead optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series for the treatment of Malaria. (PubMed, J Med Chem) - "The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies...The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for development of new antimalarial compounds."

Journal • Infectious Disease • Malaria

In vitro selection predicts malaria parasite resistance to dihydroorotate dehydrogenase inhibitors in a mouse infection model. (PubMed, Sci Transl Med) - "We investigated development of resistance by P. falciparum to the dihydroorotate dehydrogenase (DHODH) inhibitors DSM265 and DSM267 in tissue culture and in a mouse model of P. falciparum infection...We further demonstrated that the drug-resistant parasites carrying the C276Y mutation had mitochondrial energetics comparable to the wild-type parasite and also retained their fitness in competitive growth experiments. Our data suggest that in vitro selection of drug-resistant P. falciparum can predict development of resistance in a mouse model of malaria infection."

Journal • Preclinical • Infectious Disease • Malaria

A single dose combination study with the experimental antimalarials artefenomel and DSM265 to determine safety and antimalarial activity against blood-stage Plasmodium falciparum in healthy volunteers. (PubMed, Antimicrob Agents Chemother) - P1/2 | "Low level gametocytemia (1-330 female gametocytes/mL) was detected in all subjects from Day 14. The results of this single dosing combination study support the further clinical development of the use of artefenomel and DSM265 in combination as a treatment for falciparum malaria."

Clinical • Journal • Infectious Disease • Malaria

The development process for discovery and clinical advancement of modern antimalarials. (PubMed, J Med Chem) - "In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and lifecycle stage-specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development."

Clinical • Journal • Infectious Disease • Malaria • Ophthalmology

DSM265 400 mg clears asexual stage parasites but not mature gametocytes from the blood of healthy subjects experimentally infected with Plasmodium falciparum. (PubMed, Antimicrob Agents Chemother) - P1/2; "The results obtained in this study support the prediction of the efficacious dose of DSM265, and provide further evidence that DSM265 is generally safe and well tolerated. In addition, this study confirms preclinical data indicating that DSM265 permits the development and maturation of gametocytes, and does not clear mature circulating gametocytes."

Clinical • Journal

Identification and mechanistic understanding of dihydroorotate dehydrogenase point mutations in Plasmodium falciparum that confer in vitro resistance to the clinical candidate DSM265. (PubMed, ACS Infect Dis) - "X-ray structure analysis of the C276F mutant enzyme showed that conformational changes of nearby residues were required to accommodate the larger F276 residue, which in turn led to a restriction in the size of the DSM265 binding pocket. These findings underscore the importance of developing DSM265 as part of a combination therapy with other agents for successful use against malaria."

Journal