UCSF chemists have successfully redesigned a failed next-generation malaria drug to overcome critical formulation challenges that derailed its clinical development, potentially reviving hopes for a single-dose treatment against drug-resistant malaria parasites.
The research team, led by Adam Renslo, PhD, professor of pharmaceutical chemistry in the UCSF School of Pharmacy, tackled the solubility problems that plagued artefenomel, an artemisinin-inspired compound that was withdrawn from clinical trials in January 2025 despite showing promise as a potent anti-malarial agent.
Addressing Critical Drug Resistance
The urgency for new malaria treatments has intensified as artemisinin resistance, previously confined to Southeast Asia, spreads into Africa. "Now that drug resistance is in Africa, many more lives are at risk. These new molecules could give us the upper hand we need to control this deadly disease," Renslo stated.
Phil Rosenthal, MD, professor of medicine at UCSF and co-author of the study published August 8 in Science Advances, emphasized the timeline pressures: "We've tracked artemisinin resistance for years in Southeast Asia, but we're now seeing it spread to Africa, where 95% of cases and 95% of deaths occur. Given how long it takes to develop new drugs, there is widespread consensus that we need better drugs to circumvent this resistance ASAP."
Molecular Symmetry Solution
The breakthrough came from recognizing that artefenomel's highly symmetrical molecular structure caused it to form crystals that resisted dissolution. This property made the drug difficult to formulate into pills and required administration as an oral suspension that patients, particularly children, had trouble tolerating.
"Highly symmetrical molecules tend to clump into crystals that are slow to dissolve," Renslo explained. The team hypothesized that reducing the molecule's symmetry would prevent this clumping and improve solubility.
Their first successful attempt at creating a less-symmetric version validated this approach when the modified compound "disappeared immediately into a water-like solution."
Maintained Efficacy Against Resistant Strains
The optimized compound underwent comprehensive testing against malaria parasites in cellular assays, animal models, and crucially, against artemisinin-resistant parasites obtained from blood samples of malaria patients in Uganda. The results demonstrated that the redesigned molecule maintained equal potency to the original artefenomel while showing superior effectiveness compared to artemisinin against resistant parasite strains.
Clinical Advantages
The improved solubility properties address multiple clinical challenges that hindered artefenomel's development. The new formulation can be easily incorporated into pill form and combined with other anti-malarial drugs, potentially enabling the development of single-dose treatment regimens.
"For a disease like malaria, you would ideally like to cure the patient with one pill or a handful of pills and be done with it," Renslo noted. "A multi-day regimen risks missing a dose."
This represents a significant improvement over current artemisinin-based combination therapies (ACTs), which require three consecutive days of treatment to be effective.
Global Health Impact
With malaria killing approximately 600,000 people annually, most of them children in Sub-Saharan Africa, the development of effective treatments against resistant strains represents a critical global health priority. The research, funded by the National Institutes of Health, offers hope for addressing the growing threat of artemisinin resistance.
"We're optimistic that a simple chemical change like this can pave the way for an effective successor to artemisinin," Renslo concluded, "one that's cheap to make and easy to combine with other anti-malarial drugs."
