Abstract
Trypanosomatid (order Kinetoplastida)-borne neglected tropical diseases – African and American trypanosomiasis and leishmaniasis - are amongst the most devastating health threats of underdeveloped, developing and poor countries. Climatic changes due to global warming, tourism exchange and increasing migratory fluxes are re-distributing the endemic subtropical location of these diseases to a new scenario with a rising presence in developed countries during the last decades. In addition, the proved opportunistic transmission of these diseases through contaminated syringes shared by drug users, in combination with immunosuppression processes linked to HIV infections and the poor response to the typical treatments, point to AIDS patients as a sensitive sub-population prone to suffer from these diseases. DNA topoisomerases are the “molecular engineers” that unravel the DNA during replication and transcription. The mechanism of DNA unwinding includes the scission of a single DNA strand - type I topoisomerases - or both DNA strands - type II topoisomerases - establishing transient covalent bonds with the scissile end. Camptothecin and etoposide – two natural drugs whose semi-synthetic derivatives are currently used in cancer chemotherapy – target types I and II DNA-topoisomerases respectively, stabilizing ternary topoisomerase-DNA-drug covalent complexes, which irreversibly poison the enzymes. Several differences between parasite and host DNA topoisomerases have pointed to these enzymes as potential drug targets in Trypanosomatids. The unusual localization inside the mitochondria-like organellum – the kinetoplast - linked to mini and maxicircles, as well as the uncommon heterodimeric structure of the DNA topoisomerase IB subfamily, make these proteins unquestionable targets for drug intervention against trypanosomatids.
Keywords: DNA-topoisomerases, chemotherapy, camptothecin, parasitic protozoa, trypanosomatids, tropical diseases
Mini-Reviews in Medicinal Chemistry
Title: Novel Findings on Trypanosomatid Chemotherapy Using DNA Topoisomerase Inhibitors
Volume: 9 Issue: 6
Author(s): Rosario Diaz-Gonzalez, Yolanda Perez-Pertejo, Christopher Fernandez Prada, Celia Fernandez-Rubio, Rafael Balana-Fouce and Rosa M. Reguera
Affiliation:
Keywords: DNA-topoisomerases, chemotherapy, camptothecin, parasitic protozoa, trypanosomatids, tropical diseases
Abstract: Trypanosomatid (order Kinetoplastida)-borne neglected tropical diseases – African and American trypanosomiasis and leishmaniasis - are amongst the most devastating health threats of underdeveloped, developing and poor countries. Climatic changes due to global warming, tourism exchange and increasing migratory fluxes are re-distributing the endemic subtropical location of these diseases to a new scenario with a rising presence in developed countries during the last decades. In addition, the proved opportunistic transmission of these diseases through contaminated syringes shared by drug users, in combination with immunosuppression processes linked to HIV infections and the poor response to the typical treatments, point to AIDS patients as a sensitive sub-population prone to suffer from these diseases. DNA topoisomerases are the “molecular engineers” that unravel the DNA during replication and transcription. The mechanism of DNA unwinding includes the scission of a single DNA strand - type I topoisomerases - or both DNA strands - type II topoisomerases - establishing transient covalent bonds with the scissile end. Camptothecin and etoposide – two natural drugs whose semi-synthetic derivatives are currently used in cancer chemotherapy – target types I and II DNA-topoisomerases respectively, stabilizing ternary topoisomerase-DNA-drug covalent complexes, which irreversibly poison the enzymes. Several differences between parasite and host DNA topoisomerases have pointed to these enzymes as potential drug targets in Trypanosomatids. The unusual localization inside the mitochondria-like organellum – the kinetoplast - linked to mini and maxicircles, as well as the uncommon heterodimeric structure of the DNA topoisomerase IB subfamily, make these proteins unquestionable targets for drug intervention against trypanosomatids.
Export Options
About this article
Cite this article as:
Diaz-Gonzalez Rosario, Perez-Pertejo Yolanda, Prada Fernandez Christopher, Fernandez-Rubio Celia, Balana-Fouce Rafael and Reguera M. Rosa, Novel Findings on Trypanosomatid Chemotherapy Using DNA Topoisomerase Inhibitors, Mini-Reviews in Medicinal Chemistry 2009; 9 (6) . https://dx.doi.org/10.2174/138955709788452775
DOI https://dx.doi.org/10.2174/138955709788452775 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
Call for Papers in Thematic Issues
Bioprospecting of Natural Products as Sources of New Multitarget Therapies
According to the Convention on Biological Diversity, bioprospecting is the exploration of biodiversity and indigenous knowledge to develop commercially valuable products for pharmaceutical and other applications. Bioprospecting involves searching for useful organic compounds in plants, fungi, marine organisms, and microorganisms. Natural products traditionally constituted the primary source of more than ...read more
Computational Frontiers in Medicinal Chemistry
The thematic issue "Computational Frontiers in Medicinal Chemistry" provides a robust platform for delving into state-of-the-art computational methodologies and technologies that significantly propel advancements in medicinal chemistry. This edition seeks to amalgamate top-tier reviews spotlighting the latest trends and breakthroughs in the fusion of computational approaches, including artificial intelligence (AI) ...read more
Natural Products and Dietary Supplements in Alleviation of Metabolic, Cardiovascular, and Neurological Disorders
Metabolic disorders like diabetes, obesity, inflammation, oxidative stress, cancer etc, cardiovascular disorders like angina, myocardial infarction, congestive heart failure etc as well as neurological disorders like Alzheimer?s, Parkinson?s, Epilepsy, Depression, etc are the global burden. They covered the major segment of the diseases and disorders from which the human community ...read more
Natural Products in Drug Discovery
Natural products have always been one of the important ways of drug discovery due to their novel skeleton and diverse functional group characteristics. According to statistics, between 1981 and 2019, the FDA approved a total of 1,394 small molecule drugs for marketing, of which 930 marketed drugs originated from the ...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
Related Articles
-
Regulation of Innate Immunity Signaling and its Connection with Human Diseases
Current Drug Targets - Inflammation & Allergy Hypothalamic mTOR: The Rookie Energy Sensor
Current Molecular Medicine Generation of High Affinity Monoclonal Antibodies for the Prevention of HIV Infection
Recent Patents on DNA & Gene Sequences Patent Selections
Recent Patents on Drug Delivery & Formulation The Interaction Between FAK, MYCN, p53 and Mdm2 in Neuroblastoma
Anti-Cancer Agents in Medicinal Chemistry Identification of Cancerlectins by Split Bi-profile Bayes Feature Extraction
Current Proteomics Lycopene and Cardiovascular Diseases: An Update
Current Medicinal Chemistry ENaC Modulators and Renal Disease
Current Molecular Pharmacology Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options
Current Neuropharmacology Therapeutic Potential of γ -Secretase Inhibitors and Modulators
Current Topics in Medicinal Chemistry Yeast as a Powerful Model System for the Study of Apoptosis Regulation by Protein Kinase C Isoforms
Current Pharmaceutical Design Segmentation and Classification of Lung Cancer: A Review
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Targeting the Viral Nucleocapsid Protein in Anti-HIV-1 Therapy
Mini-Reviews in Medicinal Chemistry Role of MicroRNA 21 in Mesenchymal Stem Cell (MSC) Differentiation: A Powerful Biomarker in MSCs Derived Cells
Current Pharmaceutical Biotechnology Synthesis and Characterization of a New Benzoindole Derivative with Apoptotic Activity Against Colon Cancer Cells
Current Pharmaceutical Design Editorial [ Hot Topic: Cancer Therapy-Related Cardiotoxicity (Guest Editor: Maysa Abu-Khalaf and Feras Bader)]
Current Cardiology Reviews Listeria-Based Anti-Infective Vaccine Strategies
Recent Patents on Anti-Infective Drug Discovery A QSAR Study on Novel Series of Carbonic Anhydrase Inhibitors hCA IX—Tumor-Associated (Hypoxia)
Medicinal Chemistry Targeting Microparticle Biogenesis: A Novel Approach to the Circumvention of Cancer Multidrug Resistance
Current Cancer Drug Targets A Molecular Guidance System Based Upon Target Genes, Nuclear Receptors and Ligands Applied to Drug Discovery and Prediction of Toxicity
Mini-Reviews in Medicinal Chemistry