Structure-based design of novel aminopeptidase inhibitors
We are applying structure-based drug discovery approaches to the development of therapeutically useful inhibitors of two important aminopeptidase enzymes; 1) PfMAP Inhibitors. Malaria remains a global health issue. Up to 48% of the world’s population (3 billion people), now live in areas at risk of malaria. The malaria parasite Plasmodium falciparum's metalloaminopeptidases (PfMAPs), M1, M17 and M18 are essential for parasite fitness. Agents that inhibit the PfMAPs in combination is desirable as this would reduce the likelihood of parasites being able to rapidly evolve resistance.
In this project, biochemistry and protein crystallography will be used to identify how molecules are trafficked to the buried active sites of multimeric PfMAPs and SAR-guided and structure-based drug design approaches will be applied to the development of novel dual and tripeptidase inhibitors. 2) APN Inhibitors. Aminopeptidase N (APN) is a zinc-dependent aminopeptidase. APN plays a significant role in cancer proliferation, metastasis, and cancer-induced angiogenesis. Dysregulation of APN is associated with ovary, prostate, colon, kidney, and lung cancers. Inhibitors of APN can mediate cancer cell-death and have shown clinical efficacy alone and in combination chemotherapy.
The known APN inhibitors, Bestatin and Tosedostat, have shown clinical efficacy for the treatment of many cancer types including acute myeloid leukaemia and lung cancer. In our preliminary studies, we have identified a number of novel APN inhibitors, two of which demonstrate an approximate 10-fold improvement over current clinical candidates, and show sub-micromolar cellular efficacy against leukemic cell lines. This central goal of this project is to develop these compounds into potent anticancer lead compounds that possess the physicochemical properties appropriate for a drug.