Host Genetics and Responses - Project D5

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

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

State of the art:

Given the complex life cycle of the Plasmodium parasite, understanding the intricate biological processes and biochemical changes associated with life cycle progression is critical to the identification of new drug targets and the discovery of novel therapeutics. To this end, chemical biology tools, including small molecule probes for the labeling and characterization of biomolecules as well as drug-based probes for the investigation of drug localization and mode of action have the potential to enhance our understanding of parasite biology (1). Synthetic tools may likewise aid in the design and synthesis of novel antimalarial leads, including compounds with novel modes of action.

Previous own work:

We develop new chemical tools for the selective modification of biomolecules, including small molecules, peptides and proteins (2,3). Chemical strategies which are tolerant of physiological conditions have vast applications in the context of bioconjugation. As such, our current investigations aim to expand the scope of available “Click” reagents for the selective labeling of target biomolecules under mild conditions and in the absence of external catalysts (4). We are also exploring new strategies for the synthesis and modification of peptide-based proteasome inhibitors as a promising class of antimalarial leads.

Hypothesis and work plan:

The overarching aim of this project is to expand the scope and availability of chemical tools for the interrogation of Plasmodium and for the therapeutic management of malaria. Example projects include:

1.     The development of Click-based probes for the site-selective labelling of lipid species

Lipid composition of infected red blood cells changes markedly over the course of the Plasmodium life cycle (5) (Rug; Maier, ANU). New chemical strategies for the modification of lipids will be pursued to facilitate the visualization and localization of discrete lipid species throughout the life cycle. This includes the development of Click chemistry tools suitable for lipid bioconjugation and strategies for the incorporation of isotope labels and photo cross-linkers for examining lipid interactions.

2.     Synthesis of peptide-based antimalarial leads

Structural and functional differences between the human and Plasmodium proteasome opens possibilities for the application of proteasome inhibitors as novel therapies. The recent identification of peptide-based proteasome inhibitors with promising anti-malarial activity (6) warrants further investigation of peptide scaffolds for drug development. This medicinal chemistry project will involve the synthesis of recently isolated peptide natural products (e.g. macyranone A, (7)) which exhibit promising proteasome inhibitory activity and moderate antimalarial effect. Through the design, synthesis, and biological testing of structural analogues, the therapeutic potential of peptide leads will be critically examined.

Interlinkages: Alexander Maier (ANU), Melanie Rug (ANU), Brendan McMorran (ANU), Malcolm McLeod (ANU)

References:

(1) Broichhagen et al., ChemBioChem (2021), DOI: 10.1002/cbic.202000882

(2) Lin et al., Chem. Sci. (2020), 11, 10752

(3) Schwartz et al. Chem. Eur. J. (2020), 26, 2808

(4) Smyth et al., in preparation.

(5) Tran et al., Malar. J. (2016) 15:73

(6) Krishnan et al., Transl. Res. (2018), 198, 40

(7) Keller et al., J. Am. Chem. Soc. (2015), 137, 8121