Uncovering novel therapeutic solutions for antimalarial drug resistance
Abstract/Contents
- Abstract
- Emergence and spread of drug resistance against all currently used antimalarial compound classes continues to prevent eradication of malaria, one of the world's deadliest infectious diseases. To aid the effort to discover new antimalarials, we performed a phenotypic chemical screen of compound libraries provided by Medicines for Malaria: Malaria, Pathogen, Pandemic response, and Covid boxes and identified 3 compounds for follow-up. First, a non-bisphosphonate compound, MMV019313 was discovered previously in the lab to target bifunctional P. falciparum farnesyl/geranylgeranyl diphosphate synthase (PfFPPS/GGPPS), a prenyltransferase of the isoprenoid pathway. PfFPPS/GGPPS is a validated, high-priority antimalarial drug target. Unfortunately, current bisphosphonate drugs that inhibit PfFPPS/GGPPS show poor bioavailability and selectivity against the human enzymes. We generated a series of MMV019313 analogs which contained compounds that were potent, selective, and with drastically improved in vitro ADME profiles. Second, we identified a picomolar antimalarial inhibitor, MMV026468, that specifically targets the isoprenoid precursor pathway in blood-stage Plasmodium falciparum. MMV026468's action on the isoprenoid precursor pathway was validated by chemical rescue, microscopy, and western blot. Metabolite analysis demonstrated an overall decrease in isoprenoid precursor pathway intermediates. Additionally, we generated highly resistant, stable, and selective parasites against MMV026468 in three different P.falciparum strains (3D7, W2, Dd2) which underwent whole genome sequencing. Altogether we identified a promising, highly potent, pathway-specific lead compound for development of new antimalarials to combat multidrug resistant parasites. Finally, we identified MMV1580853 (previously BPH-1358), a potent and exceedingly fast-acting blood-stage antimalarial. MMV1580853's rate-of-kill mimics artemisinin in that it kills parasites equally as fast in a 1 hr pulse as treatment for a full 72 hr parasite replication cycle . MMV1580853 has been annotated as a prenyltransferase inhibitor in both humans and bacteria but did not inhibit any of the three annotated P. falciparum prenyltransferases. We did not observed buildup of ubiquitinated proteins, eIF2a phosphorylation, and hemoglobin in MMV1580853-treated parasites, indicating MMV1580853 does not have the same mechanism-of-action as either chloroquine or artemisinin, two fast-acting antimalarials used clinically. MMV1580853 also demonstrated very low mammalian cell cytotoxicity and artemisinin-resistant Kelch13 strains were equally as susceptible to MMV1580853 treatment as non-drug resistant strains. Overall, these properties make MMV150853 extremely favorable as a new lead antimalarial compound for clinical development.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Kabeche, Stephanie |
|---|---|
| Degree supervisor | Yeh, Ellen |
| Thesis advisor | Yeh, Ellen |
| Thesis advisor | Egan, Elizabeth S |
| Thesis advisor | Garten, Matthias, 1983- |
| Thesis advisor | Harbury, Pehr |
| Thesis advisor | Li, Lingyin |
| Degree committee member | Egan, Elizabeth S |
| Degree committee member | Garten, Matthias, 1983- |
| Degree committee member | Harbury, Pehr |
| Degree committee member | Li, Lingyin |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Department of Biochemistry |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Stephanie Kabeche. |
|---|---|
| Note | Submitted to the Department of Biochemistry. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/mc738ys6251 |
Access conditions
- Copyright
- © 2023 by Stephanie Kabeche
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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