Drug Discovery for Leishmaniasis (Drug Discovery, 60) - Hardcover

Hardcover

ISBN 10: 1782628894 ISBN 13: 9781782628897

Verlag: Royal Society of Chemistry, 2017

Inhaltsangabe

For human health, leishmaniasis is among the most important protozoan diseases, superseded only by malaria. Globally, 10 to 12 million people are infected with 1.5 million new cases every year. The development of cheaper new drugs is urgently needed for this neglected disease that is developing resistance to current treatments. Chemotherapy remains the only treatment option for the bulk of patients. However, this is largely unaffordable for most. In the past three years numerous advances in drug discovery have been made for treating this disease by exploiting diverging metabolic pathways between the Leishmania enzymes and their hosts, using nanotechnology to target the immune cell phagolysosomes where Leishmania resides.

Drug Discovery for Leishmaniasis aims to provide a perspective of the current treatments and their challenges, blended with the emerging strategies and methodologies that will drive new target appraisals and drug developments, as well as addressing the molecular basis of resistance in Leishmania.

Recent studies have shown that leishmaniasis affects some of the poorest people in the world, with 95% of fatal cases occurring in only 6 countries. With the WHO goal of eliminating this public health problem in the South-east Asia Region by 2020, this book will be important for anyone who is interested in neglected tropical diseases.

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Über die Autorinnen und Autoren

Dr Luis Rivas currently belongs to the scientific staff of the Center for Biological Research (Madrid, Spain) inside the Spanish National Council for Scientific Research Organization (Consejo Superior de Investigaciones Científicas, CSIC). He earned his PhD in Biochemistry (University Complutense of Madrid, 1984). After completing his PhD, he moved to the Weizmann Institute of Science, (Rehovot, Israel) and to Yale University (CT, USA) to complete his formation as a postdoctoral fellow. He focused on the design of antimicrobial peptides and on cell penetrating peptides as new drugs and vehicles for Leishmania chemotherapy. Another line is the elucidation of the mode of action of drugs targeting the bioenergetic mechanism of the parasite. He published 80 publications in referred international journals, mostly addressing Leishmania chemotherapy and molecular basis of peptide-pathogen interaction.

Dr Carmen Gil is staff scientist at Center for Biological Research of Spanish National Council for Research (CSIC) with a background in Medicinal Chemistry and Pharmacy. She received her Ph.D. from Complutense University of Madrid in 2001. After a postdoctoral appointment at Bonn University (Germany) she joined the CSIC. Her research is oriented to the discovery and development of new small-molecules as innovative target-based drugs and her research areas have been focused on phosphodiesterase and kinase inhibitors as innovative drug candidates for neurodegenerative diseases. She is involved in different projects that apply her background and experience in the development of specific parasite phosphodiesterase and kinase inhibitors in the fight for neglected parasitic diseases. She is author of more than sixty scientific publications, has four active patents in the field and has contributed to several books.

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For human health, leishmaniasis is the second most important protozoan disease, superseded only by malaria. Globally, 10 to 12 million people are infected with 1.5 million new cases every year. The development of cheaper new drugs is urgently needed for this neglected disease that is developing resistance to current treatments. Chemotherapy remains the only treatment option for the bulk of patients. However, this is largely unaffordable for most. In the past three years numerous advances in drug discovery have been made for treating this disease by exploiting diverging metabolic pathways between the Leishmania enzymes and their hosts, using nanotechnology to target the immune cell phagolysosomes where Leishmania resides.
Drug Discovery for Leishmaniasis aims to provide a perspective of the current treatments and their challenges, blended with the emerging strategies and methodologies that will drive new target appraisals and drug developments, as well as addressing the molecular basis of resistance in Leishmania.
Recent studies have shown that leishmaniasis affects some of the poorest people in the world, with 95% of fatal cases occurring in only 6 countries. With the WHO goal of eliminating this public health problem in the South-east Asia Region by 2020, this book will be important for anyone who is interested in neglected tropical diseases.

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Drug Discovery for Leishmaniasis

By Luis Rivas, Carmen Gil

The Royal Society of Chemistry

Copyright © 2018 The Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-78262-889-7

Contents

I. Appraisal of Leishmaniasis Chemotherapy, Current Status and Pipeline Strategies, 
Chapter 1 Leishmaniasis, Impact and Therapeutic Needs Jorge Alvar and Byron Arana, 3, 
Chapter 2 Anti-leishmanial Drug Discovery: Past, Present and Future Perspectives Charles E. Mowbray, 24, 
Chapter 3 From Bench to Bedside: Development and Optimization of Clinical Therapies for Visceral Leishmaniasis Fabiana Alves, Jean-Yves Gillon, Byron Arana and Thomas P. C. Dorlo, 37, 
II. Methodologies and Medicinal Chemistry Strategies to Discover and Develop New Treatments, 
Chapter 4 Drug Assay Methodology in Leishmaniasis: From the Microplate to Image Analysis Vanessa Yardley and Markella Koniordou, 57, 
Chapter 5 The Pursuit of Novel Anti-leishmanial Agents by High-throughput Screening (HTS) of Chemical Libraries Julio Martin, Juan Cantizani and Imanol Peña, 77, 
Chapter 6 Omics and Their Impact on the Development of Chemotherapy Against Leishmania Christopher Fernández-Prada, Isabel M. Vincent, Élodie Gazanion and Rubens L. Monte-Neto, 101, 
Chapter 7 In silico Tools for Target Identification and Drug Molecular Docking in Leishmania Carlos Roca, Víctor Sebastián-Pérez and Nuria E. Campillo, 130, 
Chapter 8 Medicinal Chemistry Strategies to Discover New Leishmanicidal Drugs Ana Martinez and Carmen Gil, 153, 
Chapter 9 Natural Products as a Source of New Drugs Against Leishmania João Henrique G. Lago and Andre G. Tempone, 179, 
Chapter 10 Organometallic Compounds in Chemotherapy Against Leishmania Bruno Rodrigues do Prado, Arshad Islam, Frédéric Frézard and Cynthia Demicheli, 199, 
Chapter 11 New Avenues for Drug Delivery in Leishmania: Using Treatment of Visceral Leishmaniasis with Amphotericin B as an Exemplar Katharine C. Carter and Alexander B. Mullen, 224, 
III. The Quest for Achille's Heel of Leishmania. Singular Targets as New Avenues for Drug Development, 
Chapter 12 Addressing the Molecular Biology of Leishmania for Drug Development Brianna Norris-Mullins and Miguel A. Morales, 237, 
Chapter 13 The Physical Matrix of the Plasma Membrane as a Target: The Charm of Drugs with Low Specificity Luis Rivas, Montserrat Nácher-Vázquez and David Andreu, 248, 
Chapter 14 Nutrient Transport and Sensing as Pharmacological Targets for Leishmaniasis Dan Zilberstein, 282, 
Chapter 15 Carbon Metabolism as a Drug Target in Leishmania Héctor Acosta, Meng Yuan, Ana J. Cáceres, Wilfredo A. Quiñones, Juan Luis Concepción and Paul A. M. Michels, 297, 
Chapter 16 The Redox Metabolism and Oxidative Stress in Leishmania as a Crossroads for the Lethal Effect of Drugs Helena Castro, Margarida Duarte and Ana M. Tomás, 316, 
Chapter 17 DNA Topoisomerases as Promising Targets for Leishmania Chemotherapy Rosa Ma Reguera, José M. Escudero-Martínez, Bárbara Domínguez-Asenjo, Camino Gutiérrez-Corbo and Rafael Balanã-Fouce, 348, 
Chapter 18 Molecular Basis of Drug Resistance in Leishmania Annelies Mondelaers, Sarah Hendrickx, Guy Caljon and Louis Maes, 371, 
Chapter 19 The Macrophage–Parasite Interface as a Chemotherapeutic Target in Leishmaniasis Albert Descoteaux, 387, 
Subject Index, 396, 

CHAPTER 1

Leishmaniasis, Impact and Therapeutic Needs

JORGE ALVAR AND BYRON ARANA

1.1 The Natural History of Leishmaniasis

Leishmaniasis is a group of diseases caused by a series of species of Leishmania, protozoa transmitted by the bite of infected female sand flies. The parasite in its flagellated form, called a promastigote, evades the action of complement in the bloodstream by entering mononuclear phagocytic cells (macrophages) as a result of recognition of surface ligands on the parasite by receptors in the macrophage membrane. Once inside, the parasite multiplies within a parasitophorus vacuole in a new form without a flagellum, called amastigote, by evading the oxygen cascade and other mechanisms activated by the host cell. The macrophage finally ruptures and multiple amastigotes enter new macrophages (Figure 1.1). There are two clinical forms of leishmaniasis in humans, cutaneous leishmaniasis (CL) (Box 1.1) and visceral leishmaniasis (VL) (Box 1.2). The former causes skin ulcers which normally heal spontaneously, although they may leave scars, causing stigma. The latter (also called kala-azar) affects vital organs such as the spleen, liver and bone marrow, and results in death if untreated.

In brief, cutaneous leishmaniasis is mediated by a Th1 response whereas kala-azar (visceral leishmaniasis) is mediated by a Th2 response.

In CL, T-lymphocytes initiate the cellular response, causing Th1 subpopulations to release lymphokines, including gamma interferon (IFN–?) and interleukin-2 (IL-2). These lymphokines attract macrophages to kill the parasite, and activate oxygen-dependent mechanisms and those dealing with the fusion of lysosomes with the parasitophorus vacuole. Meanwhile, the Leishmania parasite is able to neutralize this lymphokine response by releasing inhibitors of lysosome hydrolases, and of reactive oxygen species and nitrogen intermediates. Thus the parasite survives and multiplies inside the macrophage until the infection is controlled. In contrast, in VL the CD4+ T-lymphocytes stimulate Th2 subpopulations to produce IL-4, IL-5 and IL-10, meaning that macrophages are not activated and the disease progresses and invades vital organs such as the spleen, liver and bone marrow. In these cases, the cooperation of T and B cells favours development of the humoral response, with production of specific antibodies against Leishmania, but this has little effect since the parasite is hidden inside the macrophage.

Around 20 species of Leishmania cause CL but only two cause kala-azar. From an epidemiological point of view, the majority of species follow a zoonotic cycle (infected animal reservoir–sand fly–human), whereas Leishmania donovani and Leishmania tropica follow an anthroponotic cycle (infected human reservoir–sand fly–human); this difference is critical in terms of control.

Disease progress after the primary CL lesion depends on the infecting Leishmania species; patients can develop a mucocutaneous form (MCL; species belonging to the subgenus Viannia in the New World), relapse [recidivans leishmaniasis (RL) due to L. tropica], or develop diffuse cutaneous leishmaniasis (DCL; Leishmania amazonensis). In the case of L. donovani, a percentage of visceral leishmaniasis patients treated develop a skin condition named post-kala-azar-dermal leishmaniasis (PKDL), a condition not seen in visceral leishmaniasis, due to Leishmania infantum (Figure 1.2).

The natural history of leishmaniasis is determined by various elements that allow transmission, very frequently in the context of poverty, in which parasite virulence, sand fly competence and host susceptibility are key factors (Figure 1.3). Poverty is not an abstract concept but the context in which the disease flourishes, whose various components can be measured and weighted, all of them contributing to a greater or lesser extent: poor housing, deteriorated environment, low income, gender discrimination, illiteracy, lack of access to health care, malnutrition, displacement...

Details zur Ausgabe

• Verlag: Royal Society of Chemistry
• Erscheinungsdatum: 2017
• Sprache: Englisch
• ISBN 10: 1782628894
• ISBN 13: 9781782628897
• Einband: Gebundene Ausgabe
• Anzahl der Seiten: 402
• Herausgeber: Rivas Luis, Gil Carmen
• Kontakt zum Hersteller: preigu GmbH & Co. KG; mail@preigu.de; ; Lengericher Landstr. 19; Osnabrück; Niedersachsen; 49078; Deutschland