Human malaria is one of the deadliest parasitic diseases. Emerging parasite resistance to frontline anti-malarials, which inhibit key parasite proteins, has led to evolution of multi-drug resistant parasites (Cowman, Cell 2016 167(3):610)
Protein degradation, rather than inhibition, is a potent strategy for disrupting protein function. PROTACs are drugs that hijack the cell’s own machinery to degrade pathogenic proteins (Burslem, Cell 2020 181(1):102). Using anti-malarial PROTACs and the parasites own protein degradation system, we aim to destabilise functions essential for parasite survival in humans. By their unique mechanism of action, PROTACs can also bypass traditional drug resistance pathways.
To achieve these aims we will be using a combination of cutting-edge CRISPR/Cas9 mediated gene-editing of human malaria parasites, chemical biology, and structural biology.
The Cowman lab is focused on identifying the key pathways by which malaria parasites survive to cause disease in the human host. Decades of research by our group and others into the fundamental biology of parasites, anti-malarial drug action and drug resistance mechanisms employed by the parasites present us with a remarkable nexus for attacking malaria disease.
Focused on our expertise in genetic manipulation of malaria parasites and deep understanding of key pathogenic checkpoints we will also draw on the strengths of world-leading experts at WEHI in the fields of ubiquitination, proteomics and chemical biology.
Through this cross-collaborative approach, we hope to renew the activity of anti-malarial drugs against drug-resistant parasites and advance the global malaria eradication program.