Ioanna Deni
A5090300378- Malaria Research and Control
- HIV/AIDS drug development and treatment
- Computational Drug Discovery Methods
- Drug Transport and Resistance Mechanisms
- Ubiquitin and proteasome pathways
- Mosquito-borne diseases and control
- Biochemical and Molecular Research
- MicroRNA in disease regulation
- Drug-Induced Hepatotoxicity and Protection
- Tuberculosis Research and Epidemiology
- Gene Regulatory Network Analysis
- Trypanosoma species research and implications
- Cancer-related molecular mechanisms research
- Circular RNAs in diseases
- Parasites and Host Interactions
- HIV Research and Treatment
- Research on Leishmaniasis Studies
Columbia University Irving Medical Center
2021-2024
Memorial Sloan Kettering Cancer Center
2019
The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failures across Southeast Asia. In Africa, K13-propeller genotyping confirms the R561H mutation Rwanda and highlights continuing dominance wild-type K13 elsewhere. Using gene editing, we show that R561H, along with C580Y M579I, confer elevated vitro ART some African strains, contrasting minimal changes susceptibility others. M579I cause substantial...
Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential use in prophylaxis, which represents an unmet need malaria drug discovery portfolio endemic countries, particularly areas high transmission Africa. We describe structure-based computationally driven lead optimization program pyrrole-based series inhibitors,...
The Plasmodium falciparum proteasome constitutes a promising antimalarial target, with multiple chemotypes potently and selectively inhibiting parasite proliferation synergizing the first-line artemisinin drugs, including against artemisinin-resistant parasites. We compared resistance profiles of vinyl sulfone, epoxyketone, macrocyclic peptide, asparagine ethylenediamine inhibitors report that sulfones were potent even mutant parasites resistant to other did not readily select for...
Significance Here, we describe inhibitors of the Plasmodium proteasome, an enzymatic complex that malaria parasites rely on to degrade proteins. Starting from developed treat cancer, derivatives were designed and synthesized with aim increasing potency against proteasome decreasing activity human enzyme. Biochemical cellular assays identified compounds exhibit selectivity potency, both in vitro vivo, at different stages parasite’s lifecycle. Cryo-electron microscopy revealed bind a...
Multidrug-resistant Plasmodium falciparum parasites have emerged in Cambodia and neighboring countries Southeast Asia, compromising the efficacy of first-line antimalarial combinations. Dihydroartemisinin + piperaquine (PPQ) treatment failure rates risen to as high 50% some areas this region. For PPQ, resistance is driven primarily by a series mutant alleles P. chloroquine transporter (PfCRT). PPQ was reported China three decades earlier, but molecular driver remained unknown. Herein, we...
Emerging resistance to current antimalarials is reducing their effectiveness and therefore there a need develop new antimalarial therapies. Toward this goal, high throughput screens against the P. falciparum asexual parasite identified pyrazolopyridine 4-carboxamide scaffold. Structure-activity relationship analysis of chemotype defined that N1-tert-butyl group aliphatic foliage in 3- 6-positions were necessary for activity, while inclusion 7'-aza-benzomorpholine on motif resulted potent...
Widespread Plasmodium falciparum resistance to first-line antimalarials underscores the vital need develop compounds with novel modes of action and identify new druggable targets. Here, we profile five that potently inhibit P. asexual blood stages. Resistance selection studies three carboxamide-containing compounds, confirmed by gene editing conditional knockdowns, point mutations in parasite transporter ABCI3 as primary mediator resistance. Selection imidazopyridine or quinoline-carboxamide...
Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials, we conducted a phenotypic screen and identified novel tetrazole-based series that shows fast-kill kinetics relatively low propensity develop high-level Preliminary structure-activity relationships were established including identification of subseries related amides with antiplasmodial activity. Assaying parasites resistance antimalarials led us test whether the had similar mechanism action...
Circular RNAs (circRNAs) are a distinct category of single-stranded, covalently closed formed by backsplicing. The functions circRNAs incompletely known and under active investigation. Here, we report that in addition to traditional linear mRNAs (linRNA), mouse, rat, human opioid receptor genes generate exonic circRNA isoforms. Using standard molecular biologic methods, <i>Oprm1</i> (circOprm1) were detected rodent brains spinal cords, as well neuroblastoma cells, suggesting evolutionary...
Abstract The emergence of artemisinin (ART) resistance in Plasmodium falciparum parasites has led to increasing rates treatment failure with first-line ART-based combination therapies (ACTs) Southeast Asia. In this region, select mutations K13 can result delayed parasite clearance vivo and enhanced survival the ring-stage assay (RSA) vitro . Our genotyping 3,299 P. isolates across 11 sub-Saharan countries reveals continuing dominance wild-type confirms a R561H variant Rwanda. Using gene...
Abstract The emergence of artemisinin (ART) resistance in Plasmodium falciparum parasites, driven by K13 mutations, has led to widespread antimalarial treatment failure Southeast Asia. In Africa, our genotyping 3,299 isolates confirms the R561H variant Rwanda and reveals continuing dominance wild-type across 11 countries. We show that this mutation, along with M579I C580Y, confers varying degrees vitro ART African parasites. C580Y cause substantial fitness costs, which may counter-select...