Kojo Mensa-Wilmot Archives - Center for Tropical and Emerging Global Diseases

Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery

Donna Huber on January 25, 2023

The carbazole CBL0137 (1) is a lead for drug development against human African trypanosomiasis (HAT), a disease caused by Trypanosoma brucei. To advance 1 as a candidate drug, we synthesized new analogs that were evaluated for the physicochemical properties, antitrypanosome potency, selectivity against human cells, metabolism in microsomes or hepatocytes, and efflux ratios. Structure-activity/property analyses of analogs revealed …

Pseudokinase NRP1 facilitates endocytosis of transferrin in the African trypanosome

Donna Huber on November 3, 2022

Trypanosoma brucei causes human African trypanosomiasis (HAT) and nagana in cattle. During infection of a vertebrate, endocytosis of host transferrin (Tf) is important for viability of the parasite. The majority of proteins involved in trypanosome endocytosis of Tf are unknown. Here we identify pseudokinase NRP1 (Tb427tmp.160.4770) as a regulator of Tf endocytosis. Genetic knockdown of …

Hypothesis-generating proteome perturbation to identify NEU-4438 and acoziborole modes of action in the African Trypanosome

Donna Huber on October 7, 2022

NEU-4438 is a lead for the development of drugs against Trypanosoma brucei, which causes human African trypanosomiasis. Optimized with phenotypic screening, targets of NEU-4438 are unknown. Herein, we present a cell perturbome workflow that compares NEU-4438's molecular modes of action to those of SCYX-7158 (acoziborole). Following a 6 h perturbation of trypanosomes, NEU-4438 and acoziborole reduced …

Casein kinase TbCK1.2 regulates division of kinetoplast DNA, and movement of basal bodies in the African trypanosome

Donna Huber on April 16, 2021

The single mitochondrial nucleoid (kinetoplast) of Trypanosoma brucei is found proximal to a basal body (mature (mBB)/probasal body (pBB) pair). Kinetoplast inheritance requires synthesis of, and scission of kinetoplast DNA (kDNA) generating two kinetoplasts that segregate with basal bodies into daughter cells. Molecular details of kinetoplast scission and the extent to which basal body separation …

Design, Synthesis, and Evaluation of Novel Anti-Trypanosomal Compounds

Donna Huber on April 17, 2020

Human African trypanosomiasis (HAT) is a deadly neglected tropical disease caused by the protozoan parasite Trypanosoma brucei. During the course of screening a collection of diverse nitrogenous heterocycles, we discovered two novel compounds that contain the tetracyclic core of the Yohimbine and Corynanthe alkaloids, were potent inhibitors of T. brucei proliferation and T. brucei methionyl-tRNA synthetase (TbMetRS) activity. Inspired by these key …

Kinetoplast Division Factors in a Trypanosome

Donna Huber on January 10, 2019

Highlights Kinetoplasts (mitochondrial genome nucleoids) are important in bloodstream trypanosomes for the establishment of mitochondrial membrane potential. Many proteins involved in segregation of kinetoplasts have been identified. A region between a kinetoplast and basal bodies is described as a tripartite attachment complex (TAC). A set of TAC-associated proteins (TACAPs) has …

Anilinoquinoline based inhibitors of trypanosomatid proliferation

Donna Huber on November 26, 2018

Abstract We recently reported the medicinal chemistry re-optimization of a series of compounds derived from the human tyrosine kinase inhibitor, lapatinib, for activity against Plasmodium falciparum. From this same library of compounds, we now report potent compounds against Trypanosoma brucei brucei (which causes human African trypanosomiasis), T. cruzi (the pathogen that causes Chagas disease), and Leishmania spp. (which cause leishmaniasis). In addition, sub-micromolar …

Series of Alkynyl-Substituted Thienopyrimidines as Inhibitors of Protozoan Parasite Proliferation

Donna Huber on October 11, 2018

Abstract Discovery of new chemotherapeutic lead agents can be accelerated by optimizing chemotypes proven to be effective in other diseases to act against parasites. One such medicinal chemistry campaign has focused on optimizing the anilinoquinazoline drug lapatinib (1) and the alkynyl thieno[3,2-d]pyrimidine hit GW837016X (NEU-391, 3) into leads for antitrypanosome drugs. We now report …

Trainee Adds New Tool to the Trypanosome Toolbox

Donna Huber on July 19, 2018

When Ph.D. trainee Justin Wiedeman started investigating the role of protein kinase TbCK1.2, an enzyme found near the flagellum of Trypanosoma brucei, he quickly ran into a problem common to parasitologists. He needed a better tool for visualizing the membranes of this parasite. Since none of the membrane probes on the market quite did the …

New UGA Drug Discovery Core lab works to develop treatment of leading diseases

Donna Huber on November 8, 2017

Athens, Ga. – The University of Georgia has created the Drug Discovery Core laboratory, a campus-wide collaborative facility designed to hasten the development of therapeutic drugs for a number of major diseases. A survey distributed to UGA researchers in 2016 identified chemical screening and toxicity profiling as the most critical needs for enhancing drug discovery …

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