Abstract
Pathogenic protozoa threaten lives of several hundred million people throughout the world and are responsible for large numbers of deaths globally. The parasites are transmitted to humans by insect vectors, more than a hundred of infected mammalian species forming reservoir. With human migrations, HIV-coinfections, and blood bank contamination the diseases are now spreading beyond the endemic tropical countries, being found in all parts of the world including the USA, Canada and Europe. In spite of the widely appreciated magnitude of this health problem, current treatment for sleeping sickness (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi) and leishmaniasis (Leishmania spp.) remains unsatisfactory. The drugs are decades old, their efficacy and safety profiles are unacceptable. This review describes sterol 14α-demethylase, an essential enzyme in sterol biosynthesis in eukaryotes and clinical target for antifungal azoles, as a promising target for antiprotozoan chemotherapy. While several antifungal azoles have been proven active against Trypanosomatidae and are under consideration as antiprotozoan agents, crystal structures of sterol 14α-demethylases from three protozoan pathogens, Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum provide the basis for the development of new, highly potent and pathogen-specific drugs with rationally optimized pharmacological properties.
Keywords: Antiprotozoan chemotherapy, crystal structure, enzyme inhibitors, leishmaniasis, sterol 14alpha-demethylase (CYP51), sterol biosynthesis, trypanosomiasis, insect vectors, HIV-coinfections, sleeping sickness, Chagas disease, efficacy, pharmacological properties, American trypanosomiasis
Current Topics in Medicinal Chemistry
Title: Sterol 14alpha-Demethylase (CYP51) as a Therapeutic Target for Human Trypanosomiasis and Leishmaniasis
Volume: 11 Issue: 16
Author(s): Galina I. Lepesheva and Michael R. Waterman
Affiliation:
Keywords: Antiprotozoan chemotherapy, crystal structure, enzyme inhibitors, leishmaniasis, sterol 14alpha-demethylase (CYP51), sterol biosynthesis, trypanosomiasis, insect vectors, HIV-coinfections, sleeping sickness, Chagas disease, efficacy, pharmacological properties, American trypanosomiasis
Abstract: Pathogenic protozoa threaten lives of several hundred million people throughout the world and are responsible for large numbers of deaths globally. The parasites are transmitted to humans by insect vectors, more than a hundred of infected mammalian species forming reservoir. With human migrations, HIV-coinfections, and blood bank contamination the diseases are now spreading beyond the endemic tropical countries, being found in all parts of the world including the USA, Canada and Europe. In spite of the widely appreciated magnitude of this health problem, current treatment for sleeping sickness (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi) and leishmaniasis (Leishmania spp.) remains unsatisfactory. The drugs are decades old, their efficacy and safety profiles are unacceptable. This review describes sterol 14α-demethylase, an essential enzyme in sterol biosynthesis in eukaryotes and clinical target for antifungal azoles, as a promising target for antiprotozoan chemotherapy. While several antifungal azoles have been proven active against Trypanosomatidae and are under consideration as antiprotozoan agents, crystal structures of sterol 14α-demethylases from three protozoan pathogens, Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum provide the basis for the development of new, highly potent and pathogen-specific drugs with rationally optimized pharmacological properties.
Export Options
About this article
Cite this article as:
I. Lepesheva Galina and R. Waterman Michael, Sterol 14alpha-Demethylase (CYP51) as a Therapeutic Target for Human Trypanosomiasis and Leishmaniasis, Current Topics in Medicinal Chemistry 2011; 11 (16) . https://dx.doi.org/10.2174/156802611796575902
DOI https://dx.doi.org/10.2174/156802611796575902 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
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
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
-
Engineering Three-Dimensional Cardiac Microtissues for Potential Drug Screening Applications
Current Medicinal Chemistry Microtubules in Apoptosis Induction: Are They Necessary?
Current Cancer Drug Targets Lentiviral Vectors for Anti-Tumor Immunotherapy
Current Gene Therapy Hypoxia in Du-145 Prostate Cancer Xenografts After Estramustine Phosphate and Radiotherapy
Current Radiopharmaceuticals Cysteine Proteinases of Trypanosome Parasites Novel Targets for Chemotherapy
Current Drug Targets A Review of Fish Lectins
Current Protein & Peptide Science Roles of Nicotinic Acetylcholine Receptors in Stem Cell Survival/Apoptosis, Proliferation and Differentiation
Current Molecular Medicine Mannose Conjugated Starch Nanoparticles for Preferential Targeting of Liver Cancer
Current Drug Delivery The Role of Coronary Catheterization Laboratory in Post-Resuscitation Care of Patients Without ST Elevation Myocardial Infarction
Current Cardiology Reviews Ventilation During Pediatric CPR
Current Pediatric Reviews The TOLL-like / Type-I Interferon Pathways as Emerging Therapeutic Targets for Autoimmune Diseases
Drug Design Reviews - Online (Discontinued) Targeting Bacterial RNA Polymerase σ70 for Development of Broadspectrum Antisense Antibacterials
Recent Patents on Anti-Infective Drug Discovery Autophagy : Moving Benchside Promises to Patient Bedsides
Current Cancer Drug Targets Copper Complexes as Antitumor Agents: <i>In vitro</i> and <i>In vivo</i> Evidence
Current Medicinal Chemistry Allograft-Induced Proliferation of Vascular Smooth Muscle Cells: Potential Targets for Treating Transplant Vasculopathy
Current Vascular Pharmacology Isoprenoid Metabolism as a Therapeutic Target in Gram-Negative Pathogens
Current Topics in Medicinal Chemistry Targeting Tumor Microenvironment with Silibinin: Promise and Potential for a Translational Cancer Chemopreventive Strategy
Current Cancer Drug Targets Antimetastatic Activities and Mechanisms of Bisdioxopiperazine Compounds
Anti-Cancer Agents in Medicinal Chemistry Vitamin D Analogs as Anti-Carcinogenic Agents
Anti-Cancer Agents in Medicinal Chemistry Review of the Contribution of Radiolabelled Tracers for Tumour Cell Status Imaging
Current Medical Imaging