Trypanosomatids cause serious human diseases, including Chagas’ disease, leishmaniasis, and African sleeping sickness affecting millions of people, especially those from resource-limited settings. There are extremely limited treatment options for these diseases and drug resistance, toxicities, and cost are common barriers associated with existing treatments. New, more effective, safer, and cheaper treatments are urgently needed. Effective small molecule medicines, preferably per oral drugs which are stable and amenable for use in resource-constrained regions would provide accessible treatments at the point of care.
Enzymes involved in metabolism and cellular signaling are attractive druggable biological targets. Inhibitors of enzyme-based drug targets constitute ∼25% of marketed therapeutics. Notably, the folate biosynthetic enzyme, dihydrofolate reductase (DHFR), has been exploited as a successful target in the treatment of cancers and some bacterial infections. In Trypanosomatids however, there is an alternative enzyme, pteridine reductase (PTR1) which serves as a bypass route for folate biosynthesis, compensating for the function of dihydrofolate reductase (DHFR) if the latter is inhibited. Therefore, typical antifolates are ineffective in treating trypanosomatid infections. There is however a consensus that simultaneous inhibition of both protozoan DHFR1 and PTR1, ideally by a single inhibitor will constitute an effective treatment of protozoan parasitic diseases.
Recent results from our labs have revealed that these enzymes bind and sometimes react with a broad range of amine-containing compounds, using the amine functional group as the recognition motif. We have also surveyed a large volume of literature and have identified a large library of FDA/EMA-approved drugs with amine functional groups as a potential recognition site for these enzymes.
In this project, the candidate will screen a library of FDA/EMA-approved amine-containing active pharmaceutical ingredients (APIs) in current clinical use for the treatment of different diseases to identify a potent inhibitor of both protozoan PTR1 and DHFR. You will also test this compounds against another protozoal drug target, N-myristoyl transferase (NMT) Initial work will focus on in vitro screening against these enzymes and kinetic and structural studies of enzyme-inhibitor interaction. Further, in vivo studies will be performed using non-pathogenic Leishmania tarentolae and L. tropica models. The candidate will explore surface functionalization approaches using nanofabrication techniques for high-throughput screening and formulation development of the identified enzyme inhibitors targeting DHFR and PTR1. The candidate will also develop a biotechnology approach for the sustainable and green production of the identified inhibitors using enzyme toolboxes, enzyme engineering, and enzyme immobilization techniques that have been developed in our labs. We envisaged that a few lead inhibitors will progress to early clinical development and further collaboration with clinicians is anticipated. Given that the drug libraries to be screened are already currently in clinical use for the treatment of other diseases, this approach may a provide quicker route to delivering repurposed drugs for the treatment of neglected human protozoan parasitic infections.