Keywords
Plasmodium falciparum, malaria, antimalarial, antiplasmodial, kinase, inhibitor
Abstract
Malaria, a disease caused by members of the Plasmodium genus, remains a threat to global health. Despite the availability of therapeutics, Plasmodium's propensity for generating resistance-conferring mutations threatens the efficacy of these drugs. Therefore, it is essential to develop novel therapeutics, and one approach to discover such compounds is to repurpose current drugs as antimalarials. Human kinase inhibitors, most of which are developed as antineoplastics, are a valuable source of such novel compounds. Human kinase inhibitor research spans over twenty years, generating a wellspring of knowledge regarding compound design, mechanism, and tolerability that can be leveraged in the quest to develop new antiplasmodial drugs. Furthermore, the plasmodial kinome differs substantially from the human kinome, providing opportunities for selectivity and minimization of off-target effects in the host. To this end, we sought to identify and characterize compounds within human kinase inhibitor collections that have antiplasmodial effects. One library yielded a potent polo-like kinase 1 (PLK1) kinase inhibitor, BI-2536, which possessed potent antiplasmodial activity in both the asexual blood stage and liver stage and likely acts through involvement of amino acid starvation. Another library comprised exclusively of type II kinase inhibitors, designed to target kinases in the inactive conformation, produced several interesting lead compounds – TL5-135, YLIU-06-026-1, and the analog pair XMD13-99 and WZ9-034-2. These compounds were highly active against asexual blood stage parasites, killing rapidly while also possessing favorable selectivity and liver stage activity. In vivo, TL5-135 and YLIU-06-026-1 acted prophylactically by preventing infection, and therapeutically by resolving an established infection. Currently, investigations are underway to determine the mechanism of action of the lead compounds and to improve their druglike properties. In whole, this effort has not only yielded promising antiplasmodial compounds, but it also underscores the value of the repurposing approach in the quest for novel antimalarial drugs.
Completion Date
2023
Semester
Fall
Committee Chair
Chakrabarti, Debopam
Degree
Doctor of Philosophy (Ph.D.)
College
College of Medicine
Department
Burnett School of Biomedical Sciences
Degree Program
Biomedical Sciences
Format
application/pdf
Identifier
DP0028445
Language
English
Release Date
June 2029
Length of Campus-only Access
5 years
Access Status
Doctoral Dissertation (Campus-only Access)
Campus Location
Orlando (Main) Campus
STARS Citation
Bohmer, Monica J., "Repurposing of Human Protein Kinase Inhibitors Identifies Dual Stage Active Antimalarials" (2023). Graduate Thesis and Dissertation 2023-2024. 240.
https://stars.library.ucf.edu/etd2023/240
Restricted to the UCF community until June 2029; it will then be open access.