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

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

Download

Restricted to the UCF community until June 2029; it will then be open access.

Share

COinS