Millions of people are infected with Toxoplasma gondii , and the available treatment for toxoplasmosis is not ideal. Most of the drugs currently used are only effective for the acute infection, and treatment can trigger serious side effects requiring changes in the therapeutic approach.
Aspirin is a common over‐the‐counter drug used to treat pain, fever, and inflammation. It is one of the most widely used medications in the world with an estimated 35,000 metric tons produced and consumed annually. Recent research has shown that the regular ingestion of aspirin reduces a person's risk of developing colon cancer and even promotes colorectal tumor regression. Moreover, aspirin has a demonstrated ability to inhibit the proliferation of colorectal cancer cells in vitro. Although the mechanism of action has not yet been unequivocally established, it is clear that the synthesis of novel aspirin analogs is of medicinal interest. In this study, a library of aspirin analogs of varying degrees of hydrophobicity and steric hindrance were synthesized using salicylic acid as the molecular scaffold and a variety of acyl chlorides. These aspirin analogs will be screened against an array of cancer cell lines and will also be evaluated as antibacterial agents to determine their medicinal activity. The medicinal testing of this library of aspirin analogs will help to establish new structure‐activity relationships.Support or Funding InformationWe would like to thank the Department of Natural Sciences at Lawrence Technological University and the Howard Hughes Medical Institute Inclusive Excellence grant for support and funding.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Prenyldiphosphate synthases catalyze the reaction of allylic diphosphates with one or more isopentenyl diphosphate molecules to form compounds such as farnesyl diphosphate, used in e.g. sterol biosynthesis and protein prenylation, as well as longer “polyprenyl” diphosphates, used in ubiquinone and menaquinone biosynthesis. Quinones play an essential role in electron transport and are associated with the inner mitochondrial membrane due to the presence of the polyprenyl group. In this work, we investigated the synthesis of the polyprenyl diphosphate that alkylates the ubiquinone ring precursor in Toxoplasma gondii, an opportunistic pathogen that causes serious disease in immunocompromised patients and the unborn fetus. The enzyme that catalyzes this early step of the ubiquinone synthesis is Coq1 (TgCoq1), and we show that it produces the C35 species, heptaprenyl diphosphate. TgCoq1 localizes to the mitochondrion, and is essential for in vitro T. gondii growth. We demonstrate that the growth defect of a T. gondii TgCoq1 mutant is rescued by complementation with a homologous TgCoq1 gene or with a (C45) solanesyl diphosphate synthase from Trypanosoma cruzi (TcSPPS). We find that a lipophilic bisphosphonate (BPH-1218) inhibits T. gondii growth at low nM concentrations, while overexpression of the TgCoq1 enzyme dramatically reduced growth inhibition by the bisphosphonate. Both the severe growth defect of the mutant and the inhibition by BPH-1218 were rescued by supplementation with a long chain (C30) ubiquinone (UQ6). Importantly, BPH-1218 also protected mice against a lethal T. gondii infection. TgCoq1 thus represents a potential drug target that could be exploited for improved chemotherapy of toxoplasmosis.ImportanceMillions of people are infected with Toxoplasma gondii and the available treatment for toxoplasmosis is not ideal. Most of the drugs currently used are only effective for the acute infection and treatment can trigger serious side-effects requiring changes in the therapeutic approach. There is, therefore, a compelling need for safe and effective treatments for toxoplasmosis. In this work, we characterize an enzyme of the mitochondrion of T. gondii that can be inhibited by an isoprenoid pathway inhibitor. We present several evidences that demonstrate that inhibition of the enzyme is linked to parasite death. In addition, the drug is able to protect mice against a lethal dose of T. gondii. Our results thus reveal a promising chemotherapeutic target for the development of new medicines for toxoplasmosis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.