host Genetics and Drug Discovery

Project D1 - 2nd Cohort

Susceptibility to and Manifestation of Malaria: Role of Iron Deficiency and Polymorphisms of Iron Regulation

FRANK MOCKENHAUPT (Charité) in partnership with Brendan McMorran (ANU)

Iron deficiency (ID) inhibits Plasmodium growth, increases parasite phagocytosis, and reduces malaria risk. Upregulation of the iron master-regulator hepcidin due to malaria or inflammation reduces hepatic parasite survival. Several host polymorphisms influence iron status whereas hepcidin is regulated by inflammation. We have previously shown that ID as well as a common ferroportin polymorphism associate with relative resistance to malaria.

Rafael Oliviera

Project D3 -2nd Cohort

The Antiplasmodial Activity of Riboflavin Analogues

KEVIN SALIBA (ANU) in partnership with Frank Seeber (RKI, HUB)

Riboflavin (vitamin B₂) is converted into flavin mononucleotide (FMN) by riboflavin kinase, and subsequently metabolised into flavin adenine-dinucleotide (FAD) by FAD synthetase.  FMN and FAD, referred to as flavins, serve as cofactors for a number of essential enzymes. Several riboflavin analogues have been shown to possess antiplasmodial activity during the intraerythrocytic stage of the malaria parasite. We have been focusing on the antiplasmodial activity of two specific riboflavin analogues, roseoflavin and 8-amino-riboflavin. Roseoflavin has been shown to be metabolised into antimetabolites of FMN and FAD, whereas 8-amino-riboflavin appears to only be converted into an FMN antimetabolite.

TBA

Project D6 - 2nd cohort

Cholesterol as the molecular key to antiparasitic drug delivery

MALCOLM MCLEOD (ANU) in partnership with MARTIN BLUME (RKI), Alexander Maier (ANU), Melanie Rug (ANU)

The collective fight against malaria has been an ongoing battle for many thousands of years. From early naturally derived compounds, to modern synthetic drug therapies; it is a molecular siege of epic proportions which continues to take hundreds of thousands of lives each year. As the malarial parasite continues to evolve, so must our approach towards finding new strategies to combat this brutal disease. Cholesterol-drug conjugation presents itself as a new tactic to overcome poor selectivity and enhance the potency of current and emerging antimalarial drugs. Cholesterol is imported by the malarial parasite from host sources in large quantities. The mechanism by which this import occurs can by hijacked by cholesterol linked conjugates to deliver drugs to parasite targets. Understanding the molecular nature of this delivery is vital to the development of improved drug conjugates. Towards this end, a series of drug linked cholesterol analogues with a wide range of varied structural and chemical features have been synthesized to probe this transport using medicinal chemistry. Furthermore, the development of a metabolically activated fluorescent-dye conjugate has been achieved in an attempt to visualize import and metabolism of cholesterol linked constructs using microscopy. Future studies seeking to further elucidate this unlocking and entry of cholesterol into T. gondii will involve metabolomic profiling of drug-treated parasites using targeted and untargeted metabolomic studies to understand the phenotype of drug-treated parasites and the fate of drug and sterol components.

Blake Curtis

Project D7 - 2nd cohort

A Chemical Biology Toolbox for Interrogating Malaria Biology and Identifying Novel Therapeutics

LARA MALINS (ANU) in partnership with ALEXANDER MAIER (ANU), MELANIE RUG (ANU)

TBA