Trypanosomatid Cell Division Kinases

Abstract

Advances have been made recently in understanding the order of events in the cell division cycles of Leishmania spp. and Trypanosoma cruzi, adding to previous knowledge of events in Trypanosoma brucei, and highlighting similarities and differences between these trypanosomatids. However, the present understanding of how the cell cycle is regulated by kinases still largely derives from analyses in T. brucei, since convenient genetic tools for analyzing the function of essential regulators -for example, inducible expression systems and/or RNA interferenceare still lacking in Leishmania and T. cruzi. While current understanding of the function of some kinases (e.g., some cyclin-dependent kinases, the NDR kinases, aurora, tousled-like and polo-like kinases) is now very good, many more remain to be characterized, as do details of the signal transduction pathways in which they operate. A number of protein kinases have, in recent years, been genetically -and in some cases also chemically -validated as potential novel drug targets for human African trypanosomiasis or leishmaniasis, although only a few, including CRK3: CYC6, CRK3:CYCA, the NDR kinases, PK50 and PK53 and polo-like kinase, have been subjected to high-throughput screening to identify small-molecule inhibitors. However, problems with these screens include a failure to identify potent inhibitors against the parasite enzyme in vitro, a lack of selectivity for the parasite enzyme over the equivalent human enzyme, or poor efficacy against the parasite. Thus, further chemical investigations will be required to generate new compounds with more ideal properties.

Medicinal Chemistry Optimization of a Diaminopurine Chemotype: Toward a Lead for Trypanosoma brucei Inhibitors

“…Since T. brucei has been known to express essential kinases that are homologous to human kinases, − we have found that repurposing human kinase inhibitors can be successfully utilized for uncovering antitrypanosomal lead compounds. − …”