Elucidation of Dihydroquinine Mechanism(s) of Action against T. gondii

Abstract text

Daniel A. Abugri1, 2, 3*, Joseph A. Ayariga1, Melissa Boersma4, Audrey Napier1, Boakai K Robertson1,2

1Department of Biological Sciences, 2Microbiology PhD Program, 3Laboratory of Ethnomedicine, Parasitology, and Drug Discovery, College of Science, Technology, Engineering and Mathematics, Alabama State University, Montgomery, AL, 36104, 4Department of Chemistry and Biochemistry, Auburn University, Auburn, AL, 36849

* Corresponding Author: Daniel A. Abugri, Ph.D.

Email address: dabugri@alasu.edu;Tel:334-604-8158

Abstract

Dihydroquinine (DHQ) also known as hydroquinine, is a quinine-derived compound. DHQ has a history of inhibiting Plasmodium falciparum, and Plasmodium berghei, and possesses anti-arrhythmia properties. Though, previous studies in Plasmodium spp have shown its target to be nucleic acids and protein synthesis. Our team recently showed that it disrupts mitochondria membrane potential, upregulates ROS production, and depletes ATP production in T. gondii. To unify these observations with previously identified targets, we tested for the first time the effect of DHQ on T. gondii tachyzoites metabolites and lipid production in a concentration dependent manner. Interestingly, the multi-omics (metabolomics and lipidomics) studies showed that DHQ down-regulates certain lipid classes, nucleic acid precursors, and amino acid synthesis in a concentration-dependent manner. Also, for the first time, in silico analysis showed that DHQ binds strongly to DNA gyrase, Calcium Dependent Protein Kinase 1 (CDPK 1), and prolyl tRNA synthetase and thus could affect DNA replication and translational activities in T. gondii. In summary, our findings indicate that DHQ will be an effective anti-T. gondii agent and could be further developed for clinical use.

Keywords: Dihydroquinine, metabolomics, lipidomic, DNA Gyrase, tRNA Synthetase, Calcium Dependent Protein Kinases, T. gondii