Selective inhibition T2AA for human PCNA over PCNA homolog in Trypanosoma brucei

Abstract

Key words:T2 amini alcohol, Proliferating cell nuclear antigen and Trypanosoma brucei.Proliferating cell nuclear antigen (PCNA) coordinates many functions including cell cycle progression and DNA replication in eukaryotic cells. Inhibition of the PCNA protein function in Trypanosoma brucei could be a new strategy in controlling Human African Trypanosomiasis. In the present study, we explored the function of TbPCNA by deregulation the protein expression through the overexpression, and by applying the small molecule inhibition. Overexpression of human PCNA or T. brucei PCNA wildtype proteins inhibits the parasite proliferation. On the other hand, T. brucei that overexpress the HsPCNA M40A or TbPCNA M40A mutants grew normally, indicating that inhibition of PIP-box protein interaction is important for the lethal phenotype. In testing this hypothesis, we applied the small molecule inhibitor T2 amino alcohol (T2AA). Proliferation in parasites that overexpress HsPCNA resumed after T2AA treatment, but not parasites that overexpressed TbPCNA. We concluded that T2AA selectively inhibits HsPCNA not TbPCNA. This data presented here will be a prerequisite for investigating TbPCNA interacting proteins and discovering inhibitors that specifically target TbPCNA to kill the parasite.

Effect of Sofosbuvir on rats’ ovaries and the possible protective role of vitamin E: biochemical and immunohistochemical study

“…Proliferation cell nuclear antigen (PCNA) is a nonhistone protein that assists DNA polymerase which is essential for cellular replication. Its expression affects mitotic activity, so it’s usually used as an indicator for cellular proliferation [ 7 - 9 ]. The Ki-67 antigen is also a cell proliferation marker [ 10 ].…”