Identifying a next-generation antimalarial trioxolane in a landscape of artemisinin partial resistance
For over two decades, artemisinin-based combination therapy (ACT) has been the standard of care for the treatment of uncomplicated falciparum malaria. However, artemisinin partial resistance (ART-R) is now prevalent in Southeast Asia and has emerged in eastern Africa, threatening ACT efficacy. Artefenomel, a synthetic 1,2,4-trioxolane, exhibits an extended pharmacokinetic exposure profile that predicts for efficacy against ART-R parasites. Unfortunately, the development of artefenomel was halted recently after almost a decade in the clinic. Here, we describe studies of an artefenomel-adjacent chemotype that combines potent in vitro activity against clinical ART-R parasites, an extended pharmacokinetic profile with single-exposure efficacy in a murine malaria model, and enhanced stability in human microsomes and hepatocytes. Overall, our studies reveal a heretofore underexplored trioxolane chemotype with the potential to address ART-R in a next-generation trioxolane development candidate.
Authors
- Roland A. Cooper (ORCID: https://orcid.org/0000-0002-8437-9382)
- Jennifer Legac
- Stephen Orena
- Shaun D. Fontaine (ORCID: https://orcid.org/0000-0002-5800-0391)
- Poulami Talukder
- Matthew T. Klope (ORCID: https://orcid.org/0000-0002-2801-6448)
- A. B. Vinod
- Brian R. Blank (ORCID: https://orcid.org/0009-0003-4763-9856)
- Ryan L. Gonciarz (ORCID: https://orcid.org/0000-0002-6600-7032)
- Sevil Chelebieva
- Adam R. Renslo (ORCID: https://orcid.org/0000-0002-1240-2846)
- Nicholas S. Settineri (ORCID: https://orcid.org/0000-0003-0272-454X)
- Martin Okitwi (ORCID: https://orcid.org/0000-0003-2712-2174)
- Philip J. Rosenthal (ORCID: https://orcid.org/0000-0002-7953-7622)
- Patrick K. Tumwebaze (ORCID: https://orcid.org/0000-0002-5933-1432)
- Vineet Mathur
- Jeremy N. Burrows (ORCID: https://orcid.org/0000-0001-8448-6068)
- Yoweri Taremwa
- Jun Chen (ORCID: https://orcid.org/0000-0002-2362-5359)
- Grace J. Lee (ORCID: https://orcid.org/0009-0003-9729-7217)
- Priyadarshini Jaishankar (ORCID: https://orcid.org/0009-0005-2013-8941)
- A. Narayan
- Juan A. Tapia (ORCID: https://orcid.org/0000-0001-5809-0537)
Institutions
- San Francisco General Hospital (US)
- Lawrence Berkeley National Laboratory (US)
- Dominican University of California (US)
- University of California, San Francisco (US)
- Infectious Diseases Research Collaboration (UG)
- Io Therapeutics (United States) (US)
- Medicines for Malaria Venture (CH)
Publication Details
- Journal
- Science Advances
- Published
- 2025-08-08
- DOI
- https://doi.org/10.1126/sciadv.ads9168
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 0.00