Abstract
For many years, the purine salvage pathway of parasitic protozoa has been regarded as an attractive chemotherapeutic target. Parasitic protozoa lack de novo synthesis and rely entirely on the purine salvage pathway to meet their purine demands. Because of the great phylogenetic difference between parasite and host, there are often sufficient distinctions that can be exploited to design specific inhibitors for the parasitic enzymes. As a result, this pathway has been thoroughly investigated over the last twenty years. It is only quite recently that the genome studies of Trypanosoma, Leishmania and Plasmodium have been published. Based on these genomic data however, the existence of by-pass mechanisms by other enzymes and transporter systems could be suggested. Taking into account such proposition, the question might arise as to whether inhibition of a single salvage enzyme will be able or not to cause parasite death or growth arrest. In this paper, the key enzymes in the purine salvage pathways of relevant pathogenic species from the genera Trypanosoma, Leishmania and Plasmodium are reviewed. Their potential as drug targets is critically evaluated and where possible, correlated to literature data on antiparasitic activity of their inhibitors. While many studies over the past ten years have yielded contradictory results, this review attempts to clarify these findings by discussing the latest elements of progress in the field. Additionally, as part of a broader discussion on substrate analogue types of inhibitors, special attention is paid to iminoribitol derivatives, serving as transition state analogues of nucleoside-processing enzymes and comprising the most potent inhibitors reported for purine salvage enzymes. More specifically, the development of three generations of immucillins and a newer series of N-(arylmethyl-) substituted iminoribitol derivatives will be discussed. Finally, this review also covers subversive substrates of salvage enzymes: compounds that are transformed by enzymatic activity into cytotoxic agents. Although not by directly intervening in the process of purine recovery, the subversive substrate approach might deliver antiprotozoal compounds that rely on salvage enzymes for their activity.
Keywords: Purine salvage pathway, parasitic protozoa, Trypanosoma, Leishmania, Plasmodium, inhibitors, iminoribitols, nucleoside hydrolase
Current Medicinal Chemistry
Title: Inhibitors of the Purine Salvage Pathway: A Valuable Approach for Antiprotozoal Chemotherapy?
Volume: 17 Issue: 23
Author(s): M. Berg, P. Van der Veken, A. Goeminne, A. Haemers and K. Augustyns
Affiliation:
Keywords: Purine salvage pathway, parasitic protozoa, Trypanosoma, Leishmania, Plasmodium, inhibitors, iminoribitols, nucleoside hydrolase
Abstract: For many years, the purine salvage pathway of parasitic protozoa has been regarded as an attractive chemotherapeutic target. Parasitic protozoa lack de novo synthesis and rely entirely on the purine salvage pathway to meet their purine demands. Because of the great phylogenetic difference between parasite and host, there are often sufficient distinctions that can be exploited to design specific inhibitors for the parasitic enzymes. As a result, this pathway has been thoroughly investigated over the last twenty years. It is only quite recently that the genome studies of Trypanosoma, Leishmania and Plasmodium have been published. Based on these genomic data however, the existence of by-pass mechanisms by other enzymes and transporter systems could be suggested. Taking into account such proposition, the question might arise as to whether inhibition of a single salvage enzyme will be able or not to cause parasite death or growth arrest. In this paper, the key enzymes in the purine salvage pathways of relevant pathogenic species from the genera Trypanosoma, Leishmania and Plasmodium are reviewed. Their potential as drug targets is critically evaluated and where possible, correlated to literature data on antiparasitic activity of their inhibitors. While many studies over the past ten years have yielded contradictory results, this review attempts to clarify these findings by discussing the latest elements of progress in the field. Additionally, as part of a broader discussion on substrate analogue types of inhibitors, special attention is paid to iminoribitol derivatives, serving as transition state analogues of nucleoside-processing enzymes and comprising the most potent inhibitors reported for purine salvage enzymes. More specifically, the development of three generations of immucillins and a newer series of N-(arylmethyl-) substituted iminoribitol derivatives will be discussed. Finally, this review also covers subversive substrates of salvage enzymes: compounds that are transformed by enzymatic activity into cytotoxic agents. Although not by directly intervening in the process of purine recovery, the subversive substrate approach might deliver antiprotozoal compounds that rely on salvage enzymes for their activity.
Export Options
About this article
Cite this article as:
Berg M., Van der Veken P., Goeminne A., Haemers A. and Augustyns K., Inhibitors of the Purine Salvage Pathway: A Valuable Approach for Antiprotozoal Chemotherapy?, Current Medicinal Chemistry 2010; 17 (23) . https://dx.doi.org/10.2174/092986710791556023
DOI https://dx.doi.org/10.2174/092986710791556023 |
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
-
TRP Channels and Pain
Current Pharmaceutical Design Verification between Original and Biosimilar Therapeutic Antibody Infliximab Using nSMOL Coupled LC-MS Bioanalysis in Human Serum
Current Pharmaceutical Biotechnology Recent Technological Developments in Proteolytic 18O Labeling
Current Proteomics Pre-Clinical Considerations in the Assessment of Immunogenicity for Protein Therapeutics
Current Drug Safety The Development of Copper Radiopharmaceuticals for Imaging and Therapy
Medicinal Chemistry Chemical Biology: Past, Present and Future
Current Chemical Biology Advances in Quantitative Mass Spectrometry Analysis: Weighing in on Isotope Coding and Label-Free Approaches for Expression and Functional Proteomics
Current Analytical Chemistry NAMPT in Regulated NAD Biosynthesis and its Pivotal Role in Human Metabolism
Current Medicinal Chemistry Neuroprotective Appraisal of Methanolic Extract of Flowers of Nerium oleander in a Non Classical Rat Model of Alzheimer Disease
The Natural Products Journal Ionic Liquids, Microextraction Methods and Capillary Electrophoresis in Biomedical Research
Current Pharmaceutical Analysis The Antiviral and Antimalarial Drug Repurposing in Quest of Chemotherapeutics to Combat COVID-19 Utilizing Structure-Based Molecular Docking
Combinatorial Chemistry & High Throughput Screening The Application of Proteomics in Neurology
Current Proteomics Microwave Assisted Preparation of Flavylium Salts with Perchloric Acid Impregnated on Silica Gel Under Solvent-free Conditions
Letters in Organic Chemistry Small Molecule Fluorescent Probes for the Detection of Amyloid Self-Assembly In Vitro and In Vivo
Current Protein & Peptide Science “PARG Inhibitors’ Success: A Long Way to Go!”
Current Enzyme Inhibition Antimutagenic Activity of Lutein –An Oxycarotenoid Present in the Macula and its Inhibition of Cytochrome P 450 Enzymes in vitro
Drug Metabolism Letters Preparation and Characterization of Silymarin Synchronized and Sustained Release Dropping Pill
Current Drug Delivery Molecular Mechanism of Anti-tumor Effect by Triptolide in Hematological Malignancies
Current Signal Transduction Therapy Carbon Based Sample Supports and Matrices for Laser Desorption/Ionization Mass Spectrometry
Recent Patents on Nanotechnology Docking Studies for Multi-Target Drugs
Current Drug Targets