Two Research Teams Report Progress on Potential Malaria Treatments

Two Breakthroughs in the Fight Against Malaria: New Drug Candidates Show Promise

Researchers from two separate international collaborations have announced significant advances in the development of new antimalarial drug candidates. One study focuses on a new class of enzyme inhibitors, while the other reports on a compound targeting multiple stages of the parasite’s life cycle.

Development of PfAPP Enzyme Inhibitors

A team from the Universities of Bath and Leeds has developed a new class of inhibitors targeting an enzyme known as aminopeptidase P (PfAPP) from Plasmodium falciparum, the parasite responsible for the most severe form of malaria.

• The researchers created inhibitors based on the existing compound apstatin.
• These new molecules were reported to bind more strongly to the PfAPP enzyme than previous compounds and demonstrated the ability to kill the parasite in laboratory (in vitro) tests.
• Using X-ray crystallography, the team determined that the inhibitors block the enzyme’s active site, preventing it from breaking down host hemoglobin.

According to the researchers, malaria causes an estimated 282 million cases and 610,000 deaths annually. They noted that existing treatments can have side effects and are facing increasing drug resistance, which they said necessitates the development of new therapies. The PfAPP enzyme is described as essential for the parasite's growth and replication.

"Our work shows how subtle changes in inhibitor design can transform weak compounds into highly potent and selective molecules."
— Professor K. Ravi Acharya, University of Bath

"This is an important step forward in understanding how to target essential metabolic pathways in malaria parasites."
— Professor Richard Foster, University of Leeds

"By providing a detailed molecular blueprint for inhibitor design, our collaborative study lays the foundation for a new generation of drugs targeting essential parasite enzymes."
— Professor Elwyn Isaac, University of Leeds

The researchers stated that challenges remain regarding the cellular uptake of the inhibitors. They indicated that optimizing properties such as permeability will be critical for developing viable therapies.

Development of Antimalarial Compound T111

A research team led by Portland State University (PSU) has developed a chemical compound, designated T111, designed to target all three major life-cycle stages of the malaria parasite.

• Compound: T111, the development of which was reported to have taken place over 15 years.
• Target: The compound targets the liver stage, blood stage, and sexual stage (gametocytes) of Plasmodium parasites.
• Potential Application: The researchers stated T111 has the potential to become a Single Encounter Radical Cure (SERC), capable of clearing dormant liver-stage parasites that can cause relapse.
• Context: They noted that existing radical-cure drugs (tafenoquine, primaquine) have limitations and do not cover the full life-cycle profile.
• Publication: The study was published in the journal Nature Communications.
• Intellectual Property: A provisional patent application has been filed by Portland State University.

"No antimalarial currently in clinical use combines all three life-cycle properties in a single drug."
— Jane X. Kelly, Lead Researcher, PSU

"The team aims to make the production of the compound shorter, safer, and less expensive."
— Papireddy Kancharla, Associate Research Professor, PSU

The research team reported that the next steps include:

• IND-enabling studies.
• Evaluation in non-human primates in collaboration with the Walter Reed Army Institute of Research and the Armed Forces Research Institute of Medical Sciences.
• Potential collaboration with pharmaceutical companies for clinical development.

The research was conducted with collaborators from multiple institutions, including the VA Portland Health Care System, Dominican University of California, Walter Reed Army Institute of Research, University of South Florida, University of Notre Dame, National Institute of Allergy and Infectious Diseases, University of California San Francisco, SRI International, University of Melbourne, Harvard T.H. Chan School of Public Health, Oregon Health & Science University, and Howard Hughes Medical Institute.