About

Elizabeth Winzeler, Ph.D., is an expert in drug development for microbial pathogens with a focus on malaria parasites. She is the Associate Dean for Research and Innovation at the Skaggs School of Pharmacy and Pharmaceutical Sciences and a Professor in the Department of Pediatrics at the School of Medicine. Her research encompasses target discovery and validation, cheminformatics, chemistry, bioinformatics, assay development, high throughput screening, and the genetics and genomics of drug resistance. She directs the Bill and Melinda Gates Foundation-funded Malaria Drug Accelerator (MalDA), a consortium of 18 international laboratories, pharmaceutical companies, and research groups dedicated to identifying new targets and early chemical leads for malaria drug discovery. Dr. Winzeler holds a BA in Art/Natural Sciences from Lewis and Clark College, an MA in Biochemistry and Biophysics from Oregon State University, and a PhD in Developmental Biology from Stanford University. Her work has earned her numerous awards and honors, including election to the National Academy of Medicine in 2021, the ASTMH Craig Lecture in 2020, and the William Trager Award from ASTMH. She has also served as the Director of the Malaria Drug Accelerator since 2012 and has held leadership roles such as Chair of the Health Sciences Faculty Council. Her contributions significantly advance the understanding of malaria drug discovery, target validation, and strategic partnerships with industry.

Research topics

• Biology
• Genetics
• Computational biology
• Chemistry
• Pharmacology

Selected publications

• Collateral hypersensitivity between ZY19489 and piperaquine neutralizes PfCRT-mediated drug efflux and Plasmodium falciparum resistance

  Nature Communications · 2026-04-01

  articleOpen access

  New antimalarial drugs are needed to combat the current emergence and spread of Plasmodium falciparum parasite resistance to artemisinin-based combination therapies. Here, we characterize ZY19489, a triaminopyrimidine presently in a Phase Ib clinical trial. Asexual blood-stage parasites pressured with ZY19489 acquire low-grade resistance, mediated by a novel mutation in the P. falciparum chloroquine resistance transporter (PfCRT) that causes slow growth rates and a substantial fitness cost. ZY19489-resistant parasites lose their chloroquine resistance status and become hypersusceptible to piperaquine (PPQ), an artemisinin-based combination partner drug. Uptake studies in proteoliposomes loaded with drug-resistant PfCRT isoforms demonstrate that ZY19489 can block mutant PfCRT-mediated PPQ and chloroquine transport. In parasites, PfCRT mutant variants can mediate PPQ and chloroquine resistance via their efflux out of the digestive vacuole. Our findings evoke a scenario of an evolutionary trap whereby resistance to ZY19489 can block PPQ and chloroquine efflux and thereby restore their activity. Metabolomic studies show that ZY19489 leads to significantly reduced intracellular levels of short hemoglobin-derived peptides (a natural substrate of PfCRT) and accumulation of pyrimidine deoxynucleotides. Our results present a possible marker for tracking the evolution of clinical resistance to ZY19489 and a rationale for pairing this molecule with PPQ to generate a resistance-refractory combination.

  PublisherDOI

• Disruption of P. falciparum amino acid transporter elevates intracellular proline and induces resistance to Prolyl-tRNA synthetase inhibitors

  Cell chemical biology · 2025-10-01 · 1 citations

  articleOpen access
  PublisherOA PDFDOI

• Mechanistic insights into dual-active liver and blood-stage antiplasmodials

  mBio · 2025-11-24

  articleOpen access

  ABSTRACT The identification of novel antimalarials with activity against both the liver and blood stages of the parasite lifecycle would have the dual benefit of prophylactic and curative potential. However, one challenge of leveraging chemical hits from phenotypic screens is subsequent target identification. Here, we use in vitro evolution of resistance to investigate nine compounds from the Tres Cantos Antimalarial Set (TCAMS) with dual liver and asexual blood stage activity. We succeeded in eliciting resistance to four compounds, yielding mutations in acetyl CoA synthetase (AcAS), cytoplasmic isoleucine tRNA synthetase (cIRS), and protein kinase G (PKG), respectively. Using a combination of CRISPR editing and in vitro activity assays with recombinant proteins, we validate these as targets for TCMDC-125075 (AcAS), TCMDC-124602 (cIRS), TCMDC-141334, and TCDMC-140674 (PKG). Notably, for the latter two compounds, we obtained a T618I mutation in the gatekeeper residue of PKG, consistent with direct interaction with the active site, which we modeled with molecular docking. Finally, we performed cross-resistance evaluation of the remaining five resistance-refractory compounds using the Antimalarial Resistome Barcode sequencing assay (AReBar), which examined a pool of 52 barcoded lines with mutations covering >30 common modes of action. None of the five compounds where in vitro evolution of resistance was not successful yielded validated hits using AReBar, indicating they likely act via novel mechanisms and may be candidates for further exploration. IMPORTANCE Despite recent progress in the development of the next generation of antimalarial drug candidates, the risk of resistance remains. Thus, the identification of new targets that are essential at multiple stages of the malaria parasite lifecycle is an important priority. Validation of targets essential for the liver-stage not only would be relevant for prophylaxis but may also limit the potential generation of resistance due to the lower parasite numbers encountered at this stage. Here, we have leveraged compounds with dual liver- and blood-stage activity, combined with evolution of resistance, to chemically validate targets with multi-stage essentiality. We successfully evolved resistance to four, which we further characterize by genome sequencing, CRISPR editing and biochemical assays. The remaining five resistance-refractory compounds showed no interactions when profiled against a barcoded parasite library representing >30 known modes of action, suggesting these may have novel targets and represent interesting starting points for further exploration.

  PublisherDOI

• Exploration of fluorinated peptoid-based histone deacetylase inhibitors as dual-stage antiplasmodial agents

  ChemRxiv · 2025-06-23

  preprintOpen access

  In this study, we investigated the antiplasmodial properties of a series of fluorinated peptoid-capped histone deacetylase inhibitors (HDACi) against asexual blood stages of the drug-sensitive 3D7 and drug-resistant Dd2 strains of Plasmodium falciparum, as well as the exo-erythrocytic liver stages and mature gametocytes. Among the series, compound 1h emerged as the most potent derivative, showing strong activity against both P. falciparum strains (Pf 3D7 and Dd2 IC50: 0.010 μM) and against P. berghei liver stages (Pb EEF IC50: 0.74 μM), while lacking activity against mature gametocytes. Compound 1b was identified as a second hit compound with slightly lower activity against asexual blood and liver stages (Pf 3D7 IC50: 0.019 μM; Pf Dd2 IC50: 0.023 μM; Pb EEF IC50: 2.25 μM) but showed excellent parasite selectivity (SIHepG2/3D7: 2389; SIHepG2/Dd2: 1973) and notable activity against mature gametocytes (IC50: 1.70 μM). Compared to our previous hit compound MAHA-022, both 1b and 1h exhibited improved activity against asexual blood stages and enhanced parasite selectivity, albeit with reduced activity against liver stage parasites. Taken together, compounds 1b and 1h represent promising multi-stage antiplasmodial HDACi scaffolds for further development and optimization.

  PublisherOA PDFDOI

• Collateral hypersensitivity between ZY19489 and piperaquine neutralizes PfCRT-mediated drug efflux and Plasmodium falciparum resistance

  Research Square · 2025-10-09

  preprintOpen access
  PublisherOA PDFDOI

• Fungal-derived methyldeoxaphomins target <i>Plasmodium falciparum</i> segregation through the inhibition of PfActin1

  Proceedings of the National Academy of Sciences · 2025-02-18 · 1 citations

  articleOpen accessSenior authorCorresponding

  Herein we report the finding and structure determination of a natural product based on the methyldeoxaphomin scaffold family from the fungus Trichocladium asperum that shows promising antiplasmodial activity and selectivity against host cells. In vitro evolution and whole genome analysis in Plasmodium falciparum with the most potent member, NPDG-F (EC 50 of 550 nM in Dd2; 290 nM in 3D7), shows that parasite resistance to methyldeoxaphomins is strongly associated with mutations in PfActin1 (PF3D7_1246200), a critically essential ATPase needed for all stages of parasite development. Molecular docking study with available PfActin1 crystal structure shows NPDG-F occupies the same allosteric binding pocket as the known actin inhibitor cytochalasin D. The direct PfActin1 target engagement in the allosteric site was supported by cross-resistance studies, isobologram analysis with other PfActin1 inhibitors, and the structure–activity relationships for the methyldeoxaphomin family. When added to in vitro culture, NPDG-F induced morphological abnormalities in merozoite cellularization during schizogony in both the Plasmodium blood and liver stages. Our data provide chemical validation that PfActin1 is an attractive, pan-lifecycle target and inform strategies for the design of more selective inhibitors.

  PublisherOA PDFDOI

• Shared Binding Site but Divergent Resistance Profiles Uncover Novel Resistance Mechanisms in <i>Plasmodium</i> HSP90 Inhibitors

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-01

  preprintOpen accessSenior authorCorresponding

  Abstract Drug resistance is a widespread problem across therapeutic areas including malaria, but what accounts for resistance propensity remains poorly understood. Here, we reveal that two HSP90 inhibitors targeting the identical ATP-binding site exhibit dramatically different resistance profiles in P. falciparum . Geldanamycin readily selected 10 distinct resistance mutations conferring up to 22-fold resistance, while AUY-922 required 44 weeks to yield a single A41S mutation with only 2-fold resistance to AUY-922 but not to geldanamycin. Resistance mapping in parasites and yeast revealed geldanamycin resistance mutations distributed throughout the binding pocket whereas AUY-922 resistance mutations localized close to the ATP-binding site. Unexpectedly, the A41S mutation enhanced AUY-922 binding affinity without changing geldanamycin binding. In silico analysis suggested this enhancement occurs through additional hydrogen bonding, yet stronger binding correlated with resistance. In yeast, A41S had opposite effects, hypersensitizing cells to all HSP90 inhibitors tested. Additionally, conditional HSP90 knockdown increased geldanamycin sensitivity but left AUY-922 activity unaffected, indicating different target dependencies despite shared binding sites. Based on these data, we propose a multi-target hypothesis where AUY-922’s lower resistance risk stems from engaging multiple HSP90 family members. Our findings reveal how enhanced drug-target binding can paradoxically correlate with resistance and demonstrate that resistance risk cannot be predicted from binding site identity alone, providing insights for developing more durable drugs across therapeutic areas.

  PublisherOA PDFDOI

• Plasmodium falciparum protein kinase 6 and hemozoin formation are inhibited by a type II human kinase inhibitor exhibiting antimalarial activity

  Cell chemical biology · 2025-07-01 · 5 citations

  articleOpen access
  PublisherOA PDFDOI

• Plasma Lipid Metabolites, Clinical Glycemic Predictors, and Incident Type 2 Diabetes

  Diabetes Care · 2025-01-06 · 5 citations

  articleOpen access

  OBJECTIVE: Plasma metabolite profiling has uncovered several nonglycemic markers of incident type 2 diabetes (T2D). We investigated whether such biomarkers provide information about specific aspects of T2D etiology, such as impaired fasting glucose and impaired glucose tolerance, and whether their association with T2D risk varies by race. RESEARCH DESIGN AND METHODS: Untargeted plasma metabolite profiling was performed of participants in the FINRISK 2002 cohort (n = 7,564). Cox regression modeling was conducted to identify metabolites associated with incident T2D during 14 years of follow-up. Metabolites were clustered into pathways using Gaussian graphical modeling. Clusters enriched for T2D biomarkers were further examined for covariation with fasting plasma glucose (FPG), 2-h postchallenge plasma glucose (2hPG), HbA1c, or fasting insulin. Validation analyses and tests of interaction with race were performed in the Atherosclerosis Risk in Communities (ARIC) study. RESULTS: Two clusters of metabolites, representing diacylglycerols (DAGs) and phosphatidylcholines (PCs), contained the largest number of metabolite associations with incident T2D. DAGs associated with increased T2D incidence (hazard ratio [HR] 1.22; 95% CI 1.14-1.30) independent of FPG, HbA1c, and fasting insulin, but not 2hPG. PCs were inversely associated with T2D risk (HR 0.78; 95% CI 0.71-0.85) independent of FPG, 2hPG, HbA1c, and fasting insulin. No significant interaction between DAGs or PCs and race was observed. CONCLUSIONS: Fasting DAGs may capture information regarding T2D risk similar to that represented by 2hPG; PCs may capture aspects of T2D etiology that differ from those represented by conventional biomarkers. The direction of effect and strength of DAG and PC associations with incident T2D are similar across European and African Americans.

  PublisherOA PDFDOI

• Targeting Aurora Kinases as Essential Cell‐Cycle Regulators to Deliver Multi‐Stage Antimalarials Against <i>Plasmodium Falciparum</i>

  Angewandte Chemie · 2025-10-23

  articleOpen access

  Abstract Kinases play critical roles in the development and adaptation of Plasmodium falciparum and present novel opportunities for chemotherapeutic intervention. Mitotic kinases that regulate the proliferation of the parasites by controlling nuclear division, segregation, and cytokinesis. We evaluated the potential of human Aurora kinase (Aur) inhibitors to prevent P. falciparum development by targeting members of the Aurora‐related kinase (Ark) family in this parasite. Several human AurB inhibitors exhibited multistage potency (&lt; 250 nM) against all proliferative stages of parasite development, including asexual blood stages, liver schizonts, and male gametes. The most potent compounds, hesperadin, TAE684, and AT83, exhibited &gt; 1000x selectivity towards the parasite. Importantly, we identified Pf Ark1 as the principal vulnerable Ark family member, with specific inhibition of Pf Ark1 as the primary target for hesperadin. Hesperadin's whole‐cell and protein activity validates it as a unique Pf Ark1 tool compound. Inhibition of Pf Ark1 results in the parasite's inability to complete mitotic processes, presenting with unsegregated, multi‐lobed nuclei caused by aberrant microtubule organization. This suggests Pf Ark1 is the main Aur mitotic kinase in proliferative stages of Plasmodium , characterized by bifunctional AurA and B activity. This paves the way for drug‐discovery campaigns based on hesperadin targeting Pf Ark1.

  PublisherDOI

Recent grants

• Discovery of chemically validated malaria liver stage targets

  NIH · $364k · 2011–2015

• NIH Grant R21AI085374

  NIH · $519k · 2012

• NIH Grant F32HG000185

  NIH · $68k

• Discovery of long-acting, chemoprotective antimalarial compounds

  NIH · $699k · 2020–2025

• NIH Grant P50GM085764

  NIH · $46.6M · 2019

Frequent coauthors

• David Plouffe

  174 shared

• Thierry T. Diagana

  Novartis (United States)

  93 shared

• Matthias Rottmann

  91 shared

• Kelli Kuhen

  Torrey Pines Institute For Molecular Studies

  91 shared

• Suresh B. Lakshminarayana

  Novartis (United States)

  78 shared

• Reto Brun

  Swiss Tropical and Public Health Institute

  78 shared

• Christoph Fischli

  Swiss Tropical and Public Health Institute

  78 shared

• Véronique Dartois

  Hackensack Meridian Health

  75 shared

Education

• PhD, Developmental Biology

  Stanford University

  1996

Awards & honors

• Elected to the National Academy of Medicine (2021)
• ASTMH Craig Lecture (2020)
• UCSD Health Science Women Leadership Award (2020)
• Rady Children’s Hospital Awards of Excellence in Basic Resea…
• United Arab Emirates Crown Prince Count Reaching the Last Mi…