Brad Sleebs-Projects

Brad Sleebs-Projects

Researcher: 

Projects

Design of novel antimalarial agents

Malaria is a devastating disease that results in 460,000 deaths annually. Our laboratory is contributing to the global effort to develop novel small molecule therapies to treat and eliminate malaria.

Our team is currently optimising several small molecule classes identified from phenotypic screening of the malaria parasite. The antimalarial classes exert differential activity against multiple stages of the parasite’s lifecycle and therefore have potential as a prophylactic, a curative therapy or being used to eliminate malaria from endemic regions.

We are also employing chemical biology and genetic techniques to identify the mechanism of action of the small molecule classes under development.

Team members: Trent Ashton, William Nguyen

Collaborators: Alan Cowman, Helene Jousset, external collaborators and industry partners

Targeting aspartyl proteases in the malaria parasite

The malaria parasite encodes ten cathepsin D-like and one viral aspartyl protease. Our laboratory is focused on developing small molecule tools and developing genetic models to help understand the essential role of these aspartyl proteases in malaria parasite survival. This research has established the essentiality of several malaria aspartyl proteases and therefore suggesting these are attractive antimalarial drug targets.

In the next phase of our research, we have identified drug-like starting points independently targeting several essential aspartyl proteases of the malaria parasite.

Our team is currently developing these small molecule classes as potential therapeutics to treat malaria.

Team members: William Nguyen, Bethany Davey, Line Jespersen

Collaborators: Alan Cowman, Justin Boddey, Helene Jousset and an industry partner

Targeting SH2 domain proteins as a novel immune oncology therapy

Natural killer (NK) cells have emerged as a potential target in the innate immune system as they are highly toxic to tumor cells.

Interleukin 15 (IL-15) is an essential regulator and activator of NK cells. Our institute has discovered a novel checkpoint protein, CIS (cytokine-inducible SH2-containing protein), enhances NK cell response to IL-15 and thus NK cell activity. CIS is a member of the Suppressor of Cytokine Signaling (SOCS) family and negatively regulates IL-15-mediated NK cell proliferation, and therefore inhibiting CIS is a strategy to activate NK cell populations to destroy tumor cells. Our team is currently developing small molecule inhibitors of CIS as a potential immune-oncotherapy.

 

Team members: Nghi Nguyen, Iain Currie, Hao Chen

Collaborators: Sandra Nicholson, Jeff Babon, Nick Huntington, Helene Jousset and an industry partner

Targeting Epstein-Barr viral Bcl family proteins for treatment of lymphoma

Epstein-Barr virus (EBV) has been shown to be strongly associated with Burkitt’s and Hodgkin lymphomas. The EBV encodes two viral Bcl-2 proteins called BHRF1 and BALF1 that closely mimic the Bcl-2 family proteins that keep human cells alive. The viral Bcl-2 proteins are required to keep host cells alive whilst the EBV replicates.

Our institute has recently shown vBcl-2 proteins directly contribute to lymphoma tumorigenesis, thereby identifying the vBcl-2 proteins as a target for cancer therapy. We are currently optimising small molecule inhibitors targeting vBcl-2 proteins with the aim to develop a novel therapeutic for treating EBV positive lymphomas.

Collaborators: Gemma Kelly and external collaborators