ysteine proteases (CPs), also known as thiol proteases, are enzymes whose activities have been linked to viral replication and human ailments such as the Alzheimer's, Parkinson's and Huntington's disease. The immunophillin FKBP (FK506 binding protein) acts as a cis-/trans-proline isomerase and has been postulated to aid in protein folding but its enzymic activity is not related to its cellular role. Inhibitors of FKBP have been shown to be powerful immunosuppressants, chemosensitising agents, neurotrophic agents and antibiotics. This project aims to design and synthesise sulfur based isosteres as a new type of structural platform for development of specific, mechanism-based inhibitors of CPs and FKBPs. Structure-based design of full-site occupancy and stereospecific mimicry will be the basis for deriving specificity. The structure-based design will involve the parameterization of force fields appropriate for our isosteres and the application of the improved computational method to known X-ray structures of CPs and FKBPs in order to predict stereoelectronic interactions relevant to affinity and specificity. Necessary synthetic studies will ensue to construct the first-generation inhibitors. These compounds will be subjected to stability studies to provide the first quantitative evaluation on the reactivity of this class of sulfur compounds. In vitro Biological activity screening will then follow to provide 1) lead identification and 2) validation and refinement of the computational methods. Subsequent generations of inhibitors will be designed and synthesized accordingly. This work will lead to new classes of FKNBP and CP inhibitors for medicinal applications.

Animations of this work can be viewed at vislab

Scholarships for work toward a PhD, MSc, MSc(Hon) and Honours degrees are available for this and all other projects through the Australian Government (APA, APAI, RTS, IPRS), Macquarie (RAACE, iMURS, MUPGRA) or Chemistry Department (Honours Scholarships, Vacation Scholarships). Please use the links of contact the Department for more details