Researchers from the Universities of Bath and Leeds (UK) have made a significant advance in the fight against malaria by uncovering a promising new potential target for drug discovery. The findings, published in the Journal of Biological Chemistry , provide a powerful new framework for designing more effective antimalarial drugs with fewer side effects.
Malaria is a life-threatening disease caused by a parasite which is transmitted to humans through mosquito bites. It causes 282 million cases and 610,000 deaths each year worldwide.
Although there are effective treatments available, they cause side effects and drug resistance is increasing, meaning new treatments are required.
The research team focused on an enzyme called aminopeptidase P (PfAPP) from Plasmodium falciparum, the parasite responsible for the most severe form of malaria in humans.
This enzyme plays a crucial role in breaking down the human host's haemoglobin, providing essential amino acids required for its growth and replication.
By combining expertise in biology and chemistry, the Bath-Leeds team designed and developed a new class of inhibitors that dramatically outperform existing compounds that target the enzyme.
They designed a series of new inhibitors, based on an existing inhibitor called apstatin, that bind more strongly to the parasite enzyme than the original molecule.
This was visualised by X-ray crystallography techniques - where X-rays are shone through crystals of the enzyme containing each inhibitor to determine its 3D molecular structure.
The collection of structures showed that these inhibitors fit inside a pocket within the enzyme – the active site – where it would normally break down fragments of haemoglobin. The inhibitors block these fragments from getting into the active site pocket and hinder the enzyme's function.
The team showed these inhibitors not only bind more strongly than apstatin, but can also kill the parasite in vitro, making them promising candidates for drug development.
Professor K. Ravi Acharya, from the University of Bath's Department of Life Sciences and corresponding author of the study, said: "Our work shows how subtle changes in inhibitor design can transform weak compounds into highly potent and selective molecules.
"Importantly, we were able to visualise the enzyme with these inhibitors bound to it, allowing us to directly observe the molecular interactions that drive their activity."
The co-authors at the University of Leeds included chemist Professor Richard Foster, and biologists Professors Elwyn Isaac and Glenn McConkey.
Professor Foster said: "This is an important step forward in understanding how to target essential metabolic pathways in malaria parasites.
"By defining the structural rules for selectivity, we can now design inhibitors that are both more effective and safer."
Despite the high potency of the newly developed inhibitors in biochemical assays, the researchers also identified challenges related to cellular uptake, highlighting the importance of optimising drug-like properties such as permeability. Addressing these factors will be critical in translating these discoveries into viable antimalarial therapies.
Professor Isaac said: "Malaria remains a major global health challenge, with growing resistance to existing treatments posing an increasing threat.
"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."
