Chagas’ disease and leishmaniasis are two neglected tropical diseases of the world that lack effective therapeutic treatment options and cause life-threatening complications. A need exists for new and improved drug options for both diseases. Our laboratory recently identified a cluster of hits having the same core scaffold from a high-throughput screen (HTS), which inhibits Trypanosoma cruzi glucokinase (TcGlcK) quite well (e.g. two inhibitors had IC50 values in the low micromolar range). TcGlcK is a potential drug target of the T. cruzi protozoan parasite because it is an enzyme found at a nodal point between two critically important metabolic pathways, glycolysis and the pentose phosphate pathway. Compounds of the identified cluster belonged to the 3-nitro-2-phenyl-2H-chromene scaffold, and in this study, a small chemical library of analogues were purchased from commercially available suppliers that were subsequently tested against two trypanosomatid glucokinases, TcGlcK and Leishmania braziliensis glucokinase (LbGlcK) for the purpose of searching for improved inhibitors. TcGlcK and LbGlcK share a 44% protein sequence identity, and with enough differences between the two glucokinases, inhibitors of the chemical library are likely to inhibit at different magnitudes. The purchased compounds all had one-point changes from one of the hit-to-lead candidates of our TcGlcK HTS campaign and the analysis will aid in the understanding of which regions of the core scaffold are important for inhibition. Most of the compounds examined in the primary screen of TcGlcK were determined to be hits and the primary screening results of compounds against LbGlcK will be reported in due course.
Edward L. D'Antonio
Garrett B. Conner and Edward L. D'Antonio
About This Project
An estimated 6 – 7 million people in Latin America and 300,000 U.S. citizens are infected with the protozoan parasite Trypanosoma cruzi that results in Chagas’ disease, a neglected tropical disease (NTD). Principally spread by the kissing bug (cover image), there exists an urgent need for development of new therapeutics to replace the outdated clinically used drugs, benznidazole and nifurtimox. Our research focuses on the discovery of novel antichagasic compounds for improved medicine.
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What is the context of this research?
Chagas' disease is an NTD that causes cardiomyopathy and the enlargement of other organs that eventually leads to death in the patient. Such symptoms occur 10 - 20 years after being infected. Essential enzymes for the survival of T. cruzi cells include the glucose kinases, T. cruzi glucokinase (TcGlcK) and T. cruzi hexokinase (TcHxK). These enzymes present a drug discovery targeting opportunity for potent inhibitors to replace benznidazole and nifurtimox usage. In 2016, we began a collaboration with the Cordeiro Lab (Laboratório Nacional de Biociências in Campinas, Brazil), in which a high-throughput screening (HTS) campaign against TcGlcK was conducted and a promising core scaffold was identified. My laboratory will now perform a SAR expansion to identify a more potent analogue.
What is the significance of this project?
Benznidazole and nifurtimox were developed in the early 1970s, but yield significant burdensome side-effects. New and safe drugs are needed for a practical treatment program, especially for children. Our proposed research aims at identifying viable drug leads with the SAR approach. As we determine more TcGlcK and TcHxK inhibitors identified from the primary screens, we will compare the hits to our first HTS campaign. It is expected that the primary screens against the T. cruzi glucose kinases should reveal more potent analogues. This contribution is significant because it is expected to lead to a new therapeutic candidate that will surpass the effectiveness of benznidazole and/or nifurtimox in clinical trials.
What are the goals of the project?
The principal goal for the project is to screen potential enzyme inhibitors of the T. cruzi glucose kinases (TcGlcK and TcHxK) that are essential drug targets of the parasite. The analogue compounds we plan to purchase will have a high 3-dimensional similarity to the previously identified hit from our HTS experimentation. Ultimately, effective inhibitors will lead to T. cruzi cellular apoptosis and the determination of validated hits will be extremely beneficial since new starting points for drug leads will become available. Once we learn which compounds inhibit TcGlcK and/or TcHxK very well, we will determine if there is a correlation with the in vitro biological assays, which is critical for the early-stage drug discovery process.
The anti-T. cruzi biological testing will demonstrate which compounds are most effective of the series being evaluated. This preliminary data can then be used as a basis for a larger grant.
(a) Preparing a supply of purified enzyme (TcGlcK & TcHxK) (Sept. 2018).
(b) Running primary screens of analogues vs. enzymes (Oct. – Nov. 2018).
(c) Performing counter-screens (Nov. – Dec. 2018).
(d) Running enzyme – inhibitor kinetics on validated hits (Jan. – Apr. 2019).
(e) Submitting 15 analogues for in vitro biological testing against T. cruzi (Jan. 2019).
(f) Data analysis (Apr. 2019).
Jul 09, 2018
Sep 10, 2018
Data collection begins
Apr 05, 2019
Data collection ends
Apr 08, 2019
Meet the Team
Dr. Edward L. D'Antonio
My training is in Chemistry and I received my Ph.D. at North Carolina State University in 2010. I have published a total of 19 scientific articles/patents, I have received approx. $60,000 in research support since 2013, and I have also mentored 21 undergraduates at USC Beaufort.
My Webpage: www.uscb.edu/edant
I manage the environmental organization at my university that usually has approximately 15 active members in a given year and I am in my second year now. I have selected projects that are directed towards making a difference at our county's level (Beaufort County). As we complete more projects, I want to focus on helping more of the towns in the coastal region of South Carolina. There exists a vast number of environmental challenges, but my focus has centered on solid waste management and recycling. The introduction of a new recycling program or the improvement of an existing one helps bring us a step forward in the right direction in environmental stewardship. I believe that such practices should be exemplified beginning at universities and school systems because students at any level will learn by example.
I have a strong interest in sustainability. When I was younger, I used to see trash on the side of the road by my house, which included Styrofoam cups, plastic cups, and soda bottles among other things (in the early 1990s). My brothers and I would routinely pick up that trash to make our surroundings of our home look better. Those experiences of trash pickups have forever stayed with me, but also, as a long-distance runner, I have always observed litter on the sides of the roads too. In addition to being a researcher, I have devoted part of my effort in helping the community in which I live. My goal is to make a difference for our county and to inspire others to take on such a sustainable responsibility. In this way, towns will be cleaner. Finally, the projects I am choosing will help in reducing the carbon footprint and landfill capacity.
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