A previously undiscovered target for treating malaria could pave the way for a new generation of drugs, experts say.  

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. 

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. 

It is hoped the discovery could help develop new drugs to combat malaria, a life-threatening disease which causes 610,000 deaths each year worldwide. Although effective treatments are available, they often cause side effects and, with drug resistance increasing, new treatments are required. 

“This is an important step forward in understanding how to target essential metabolic pathways in malaria parasites,” said Professor Richard Foster, chemist at the University of Leeds and Co-Author of the study. 

“By defining the structural rules for selectivity, we can now design inhibitors that are both more effective and safer.” 

 “Malaria remains a major global health challenge, with growing resistance to existing treatments posing an increasing threat,” added Professors Elwyn Isaac, biologist at the University of Leeds and study Co-Author. 

“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.” 

Crystallography techniques signpost future antimalarial therapies
 

As part of the study, researchers 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. 

“Our work shows how subtle changes in inhibitor design can transform weak compounds into highly potent and selective molecules,” said Professor K Ravi Acharya from the University of Bath’s Department of Life Sciences and Corresponding Author of the study. 

 “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.” 

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 could be critical in translating these discoveries into viable antimalarial therapies.