Research Activities

The scientific activities are grouped into five clusters:

Cluster 1 – Novel aminoquinolines

The digestive food vacuole (DV) of the malarial parasite is a critical organelle in the life of the parasite. Its principal role appears to be associated with the digestion of host erythrocyte haemoglobin. Hemoglobin is delivered to the DV via a modified endocytic pathway. Under the influence of a series of protease enzymes the haemoglobin is systematically digested into smaller peptides for ultimate use by the parasite and heme or ferriprotoporphyrin IX (FP) which is toxic in its free form. In the malaria parasite, FP is oxidised and dimerized to beta hematin before biocrytstallization into haemozoin or malarial pigment, which is non-toxic to the parasite (Fitch and Kanjananggulpan, 1987; Egan et al., 2002). This process is of importance because it is unique to the malaria parasite and it is already a proven target for chemotherapy. The quinoline and the endoperoxide based AntiMalarials have mechanisms of action intimately linked with the process of haemoglobin digestion. Furthermore this protease enzymes involved in the degradation have been identified as possible targets for chemotherapy. The DV also has less well-defined functions including Ca ++ homeostasis, drug resistance (via pfcrt and pfMDR1) and volume control, which themselves offer chemotherapeutic opportunities. We propose the development of a series of chemotherapeutic candidates that target processes within the DV exploiting our knowledge of the organelle and existing drugs effective at this site.

Objective: to produce a novel aminoquinoline capable of evaluation in man in 5 years


Cluster 2 – Novel peroxides

The peroxide drug class represent another AntiMalarial class targeting the parasites food vacuole. These excellent AntiMalarials suffer from reliance on semi-synthetic synthesis, poor dispositional characteristics and the operational need to be used in combination with another unrelated AntiMalarial. This cluster aims at improving on existing peroxides based on a number of novel approaches.

Objective: to produce a novel peroxide capable of evaluation in man within 5 years


Cluster 3 – Lipid targets

Lipid biogenesis in Plasmodium includes all the metabolic processes that are responsible for the synthesis of the membranes that serve as permeability barriers between the parasite and its host, the membranes of the subcellular organelles, the membrane networks in the cytoplasm of infected erythrocytes, and the lipid-derived signalling molecules that regulate parasite development and proliferation. Lipids are among the most critical components that need to be duplicated, and there is considerable evidence supporting the crucial role of lipids and the enzymes involved in their synthesis in parasite growth, differentiation and various other cellular events such as signalling and hemozoin formation. The intracellular malarial parasites meet their demand for the necessary lipid species by active synthesis through de novo pathways using precursors that are actively transported from the host cytoplasm. A new antimalarial pharmacological approach based on inhibition of the plasmodial phosphatidylcholine biosynthesis, the major plasmodial phospholipid, has been developed. Bisquaternary drugs mimic choline structure, inhibit de novo phosphatidylcholine biosynthesis and cure highly malarial infected mice or monkey. Compounds cure at low doses, avoid recrudescence and retain full activity after a single injection. Besides, the Plasmodium has evolved unique features in lipid biogenesis to survive within the intraerythrocytic environment, thus prompting a growing interest in lipid metabolism to identify rational targets for malaria chemotherapy.

Objective: to produce a novel lipid targeting drug of evaluation in man within 5 years


Cluster 4 – Discovery

The cytosol is the site of a number of metabolic and signalling pathways, many of which are likely to be essential for parasite survival. The work proposed for this cluster includes potential targets in both types of pathways. With respect to metabolic pathways: Potential inhibitors of lactate dehydrogenase (LDH) were identified in silico, and subsequently shown to have good levels of activity against the parasite, but low effect on LDH. The molecular target of these compounds now requires identification, and the pharmacokinetics of the compound need to be improved. Enzymes involved in Thiamine pyrophosphate (TPP) synthesis represent potential targets, as this cofactor is essential to many important enzymatic activities. One of the enzymes required for TPP synthesis (hydroxyethylthiazole kinase) has been identified and cloned by one of the laboratories of the cluster, and work is proposed to express this enzyme so as to allow biochemical characterisation and chemical library screening. With respect to signalling pathways, the cluster includes a laboratory that has brought significant contribution to the identification and characterisation of protein kinases belonging to families known to be essential for signal transduction (e.g. MAPKs) and/or cell cycle control (e.g. CDKs). Several of these enzymes have been expressed in E.coli and are active in vitro as recombinant proteins. Two work packages concern the validation of these protein kinases as drug target through reverse genetics approaches, and medium-throughput screening of a 12000 compound library on these three kinases, respectively. In addition to the targets being exploited above the parasite genome has confirmed the existence of a large number of transporters, some involved in drug resistance, which we have failed to exploit as chemotherapeutic targets. Equally the value of the mitochondria as a proven target has not been fully exploited. Work packages within this cluster will begin to probe these areas.

Objective: to produce a novel inhibitor of essential parasite function capable of evaluation in man within 5 years


Cluster 5 – Platform activities

This cluster provides support to the consortium workpackages to aid lead identification

Objective: to provide support on efficacy evaluation for lead identification and for combination drugs.