Abstract
Atoxyl, the first medicinal drug against human African trypanosomiasis (HAT), also known as sleeping sickness, was applied more than 100 years ago. Ever since, the search for more effective, more specific and less toxic drugs continued, leading to a set of compounds currently in use against this devastating disease. Unfortunately, none of these medicines fulfill modern pharmaceutical requirements and may be considered as therapeutic ultima ratio due to the many, often severe side effects. Starting with a historic overview on drug development against HAT, we present a selection of trypanosome specific pathways and enzymes considered as highly potent druggable targets. In addition, we describe cellular mechanisms the parasite uses for differentiation and cell density regulation and present our considerations how interference with these steps, elementary for life cycle progression and infection, may lead to new aspects of drug development. Finally we refer to our recent work about CNS infection that offers novel insights in how trypanosomes hide in an immune privileged area to establish a chronic state of the disease, thereby considering new ways for drug application. Depressingly, HAT specific drug development has failed over the last 30 years to produce better suited medicine. However, unraveling of parasite-specific pathways and cellular behavior together with the ability to produce high resolution structures of essential parasite proteins by X-ray crystallography, leads us to the optimistic view that development of an ultimate drug to eradicate sleeping sickness from the globe might just be around the corner.
Keywords: Apoptosis, autophagy, drug development, human african trypanosomiasis, sleeping sickness, Trypanosoma brucei.
Current Medicinal Chemistry
Title:Drug Development Against Sleeping Sickness: Old Wine in New Bottles?
Volume: 21 Issue: 15
Author(s): J. Stein, S. Mogk, C.N. Mudogo, B.P. Sommer, M. Scholze, A. Meiwes, M. Huber, A. Gray and M. Duszenko
Affiliation:
Keywords: Apoptosis, autophagy, drug development, human african trypanosomiasis, sleeping sickness, Trypanosoma brucei.
Abstract: Atoxyl, the first medicinal drug against human African trypanosomiasis (HAT), also known as sleeping sickness, was applied more than 100 years ago. Ever since, the search for more effective, more specific and less toxic drugs continued, leading to a set of compounds currently in use against this devastating disease. Unfortunately, none of these medicines fulfill modern pharmaceutical requirements and may be considered as therapeutic ultima ratio due to the many, often severe side effects. Starting with a historic overview on drug development against HAT, we present a selection of trypanosome specific pathways and enzymes considered as highly potent druggable targets. In addition, we describe cellular mechanisms the parasite uses for differentiation and cell density regulation and present our considerations how interference with these steps, elementary for life cycle progression and infection, may lead to new aspects of drug development. Finally we refer to our recent work about CNS infection that offers novel insights in how trypanosomes hide in an immune privileged area to establish a chronic state of the disease, thereby considering new ways for drug application. Depressingly, HAT specific drug development has failed over the last 30 years to produce better suited medicine. However, unraveling of parasite-specific pathways and cellular behavior together with the ability to produce high resolution structures of essential parasite proteins by X-ray crystallography, leads us to the optimistic view that development of an ultimate drug to eradicate sleeping sickness from the globe might just be around the corner.
Export Options
About this article
Cite this article as:
Stein J., Mogk S., Mudogo C.N., Sommer B.P., Scholze M., Meiwes A., Huber M., Gray A. and Duszenko M., Drug Development Against Sleeping Sickness: Old Wine in New Bottles?, Current Medicinal Chemistry 2014; 21 (15) . https://dx.doi.org/10.2174/0929867320666131119121636
DOI https://dx.doi.org/10.2174/0929867320666131119121636 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...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
Related Articles
-
Drainage of Cerebral Abscesses Prior to Valve Replacement in Stable Patients with Acute Left-Sided Infective Endocarditis
CNS & Neurological Disorders - Drug Targets Intimal Hyperplasia in Murine Models
Current Drug Targets Potentiation of Anti-Cancer Treatment by Modulators of Energy Metabolism
Current Pharmaceutical Biotechnology Patent Selections:
Recent Patents on Cardiovascular Drug Discovery Postoperative Care of the Transplanted Patient
Current Cardiology Reviews Estrogen Regulation of MicroRNA Expression
Current Genomics Identification of Drug Candidates for Breast Cancer Therapy Through Scaffold Repurposing: A Brief Review
Current Drug Research Reviews Recent Advancements in Diagnosis and Therapy of Liver Cirrhosis
Current Drug Targets The Immunologic Barriers to Replacing Damaged Organs
Current Immunology Reviews (Discontinued) Substituted Benzimidazole Derivatives as Angiotensin II -AT1 Receptor Antagonist: A Review
Mini-Reviews in Medicinal Chemistry Most Efficient Routes for the Synthesis of α,β-Diamino Acid-Derived Compounds
Current Pharmaceutical Design Integrins: A Method of Early Intervention in the Treatment of Colorectal Liver Metastases
Current Pharmaceutical Design Therapeutic Potential of Erythropoietin in Retinal and Optic Nerve Diseases
CNS & Neurological Disorders - Drug Targets Recent Patents on Rho Signaling Pathway as Therapeutic Target for Cardiovascular Diseases
Recent Patents on Cardiovascular Drug Discovery Adverse Consequences of Right Ventricular Apical Pacing and Novel Strategies to Optimize Left Ventricular Systolic and Diastolic Function
Current Cardiology Reviews The Guanylyl Cyclase Inhibition by MB as Vasoplegic Circulatory Shock Therapeutical Target
Current Drug Targets Impact of Red Wine Consumption on Cardiovascular Health
Current Medicinal Chemistry Biomarkers in Cardiomyopathies and Prediction of Sudden Cardiac Death
Current Pharmaceutical Biotechnology Regulators of Chemokine Receptor Activity as Promising Anticancer Therapeutics
Current Cancer Drug Targets New Technologies: Non-Hormonal Female Contraception
Current Women`s Health Reviews