A novel therapeutic to treat malaria

A novel therapeutic to treat malaria

Partnering opportunity in infectious disease:

A novel therapeutic to treat malaria

 

Team

Professor Alan Cowman, Associate Professor Justin Boddey, Dr Brad Sleebs

Background

Malaria is caused by the Plasmodium parasite. The most virulent form, P. falciparum, accounts for 70 per cent of infections.

Malaria parasites survive inside human red blood cells by exporting hundreds of proteins to remodel it. Approximately 450 proteins are exported by trafficking through the parasite Endoplasmic Reticulum (ER) and possess a N-terminal export motif, termed the Plasmodium export element (PEXEL), which targets the proteins to the erythrocyte.

In order for proteins to be correctly exported, the PEXEL motif must be processed by an ER-resident aspartic acid protease called Plasmepsin V (PMV).

We have previously identified that PMV is critical for the export of proteins from the malaria parasite. As such, development of therapeutics inhibiting PMV may lead to novel anti-malarial therapeutics.

The technology

Our researchers have developed probes that mimic the PEXEL substrate and are highly potent and selective inhibitors of PMV. The mimetics display strong inhibition of PMV with negligible off-target activity against human proteases, confirming that the export pathway is conserved in Plasmodium species.

We have obtained an X-ray crystal structure of PMV bound to a probe molecule and for the first time have demonstrated that the treatment of P. falciparum parasites in culture with the small molecule probe causes a reduction in PEXEL processing, protein export and subsequently results in parasite death.

The PEXEL mimetic probe is currently being further optimised by a structure-guided approach, and will be used to further understand the role of PMV in liver and transmission stages of the parasite lifecycle. Analogues are also being synthesised and tested in vitro.

Further, high-throughput screening and validation of a compound library that possesses anti-malarial properties has been performed to identify inhibitors of PMV, and a single drug-like class of eight compounds has been identified.

Medicinal chemistry efforts have established an early structure activity relationship, and researchers are currently focusing on improving the potency of the lead class.

Applications

Malaria is a global public health burden, with worldwide infections into the hundreds of millions, and deaths of approximately one million people annually.

Intellectual property

The PMV structure is protected by a provisional patent, and compound structures have not been publicly disclosed. An opportunity exists to generate novel composition of matter intellectual property.

Opportunity for partnership

We are seeking a partner to co-develop the drug-like series that will not only target blood stage malaria, but potentially liver and transmission stages of malaria. The ultimate goal is to develop an anti-malarial drug that possesses the appropriate potency, safety and pharmacokinetic profiles.

Key publications

  • Hodder AN. et al. Structural basis for plasmepsin V inhibition that blocks export of malaria proteins to human erythrocytes. Nat Struct Mol Biol. 2015 Aug;22(8):590-6 PMID: 26214367
  • Sleebs B. et al. Inhibition of plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites. PLoS Biol. 2014 Jul 1;12(7):e1001897 PMID: 24983235
  • Sleebs B. et al. Transition state mimetics of the Plasmodium export element are potent inhibitors of plasmepsin V from P. falciparum and P. vivax. J Med Chem. 2014 Sep 25;57(18):7644-62 PMID: 25167370
  • Boddey JA. et al. An aspartyl protease directs malaria effector proteins to the host cell. Nature. 2010 Feb 4;463(7281):627-31 PMID: 20130643
  • Russo I. et al. Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte. Nature. 2010 Feb 4;463(7281):632-6. PMID: 20130644

Contact

Dr David Segal, Technology Development Associate

Phone: +61 3 9345 2418 Email: segal@wehi.edu.au

 

Other partnering opportunities in infectious disease