Abstract
Trypanosomatids are the causative agents of African sleeping sickness, Chagas disease and the three forms of leihmaniasis. New drugs against these parasitic protozoa are urgently needed since the currently available chemotherapy is not at all satisfying. One promising approach towards the development of new drugs is based on the design of specific enzyme inhibitors. Trypanosomes and leishmania possess a unique thiol metabolism in which the ubiquitous glutathione / glutathione reductase system is replaced by trypanothione and trypanothione reductase. The dithiol trypanothione is the key molecule for the synthesis of DNA precursors, the homeostasis of ascorbate, the detoxification of hydroperoxides, and the sequestration / export of thiol conjugates. Synthesis and reduction of trypanothione are essential for the maintenance of a reducing intracellular milieu which renders the respective enzymes attractive drug target molecules. Here we present the current state of knowledge of the thiol metabolism of trypanosomatids, comprising the trypanothione / tryparedoxin, thioredoxin, and ovothiol systems of the parasites. The most effective inhibitors of the enzymes known to date, their mode of action, and the (dis)advantages of different types of inhibitors as potential drug candidates will be discussed.
Keywords: antitrypanosomal drug development, trypanothione metabolism, biosynthesis of trypanothione
Current Topics in Medicinal Chemistry
Title: Enzymes of the Trypanothione Metabolism as Targets for Antitrypanosomal Drug Development
Volume: 2 Issue: 11
Author(s): Armin Schmidt and R. Luise Krauth-Siegel
Affiliation:
Keywords: antitrypanosomal drug development, trypanothione metabolism, biosynthesis of trypanothione
Abstract: Trypanosomatids are the causative agents of African sleeping sickness, Chagas disease and the three forms of leihmaniasis. New drugs against these parasitic protozoa are urgently needed since the currently available chemotherapy is not at all satisfying. One promising approach towards the development of new drugs is based on the design of specific enzyme inhibitors. Trypanosomes and leishmania possess a unique thiol metabolism in which the ubiquitous glutathione / glutathione reductase system is replaced by trypanothione and trypanothione reductase. The dithiol trypanothione is the key molecule for the synthesis of DNA precursors, the homeostasis of ascorbate, the detoxification of hydroperoxides, and the sequestration / export of thiol conjugates. Synthesis and reduction of trypanothione are essential for the maintenance of a reducing intracellular milieu which renders the respective enzymes attractive drug target molecules. Here we present the current state of knowledge of the thiol metabolism of trypanosomatids, comprising the trypanothione / tryparedoxin, thioredoxin, and ovothiol systems of the parasites. The most effective inhibitors of the enzymes known to date, their mode of action, and the (dis)advantages of different types of inhibitors as potential drug candidates will be discussed.
Export Options
About this article
Cite this article as:
Schmidt Armin and Krauth-Siegel Luise R., Enzymes of the Trypanothione Metabolism as Targets for Antitrypanosomal Drug Development, Current Topics in Medicinal Chemistry 2002; 2 (11) . https://dx.doi.org/10.2174/1568026023393048
DOI https://dx.doi.org/10.2174/1568026023393048 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
AlphaFold in Medicinal Chemistry: Opportunities and Challenges
AlphaFold, a groundbreaking AI tool for protein structure prediction, is revolutionizing drug discovery. Its near-atomic accuracy unlocks new avenues for designing targeted drugs and performing efficient virtual screening. However, AlphaFold's static predictions lack the dynamic nature of proteins, crucial for understanding drug action. This is especially true for multi-domain proteins, ...read more
Artificial intelligence for Natural Products Discovery and Development
Our approach involves using computational methods to predict the potential therapeutic benefits of natural products by considering factors such as drug structure, targets, and interactions. We also employ multitarget analysis to understand the role of drug targets in disease pathways. We advocate for the use of artificial intelligence in predicting ...read more
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements