Drug Discovery for Leishmaniasis: 60 - Rilegato

Rilegato

ISBN 10: 1782628894 ISBN 13: 9781782628897

Casa editrice: Royal Society of Chemistry, 2017

Riassunto

For human health, leishmaniasis is among the most important protozoan diseases, superseded only by malaria.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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Dalla quarta di copertina

For human health, leishmaniasis is the second most important protozoan disease, superseded only by malaria.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 and war, etc. More than 20 000 patients with visceral leishmaniasis die without treatment, women more frequently than men, and those with cutaneous or mucocutaneous leishmaniasis are highly stigmatized and excluded from society. Families with a member suffering from leishmaniasis incur debt or sell belongings to pay for treatment, digging themselves further into poverty. Oblivion facilitates leishmaniasis, and leishmaniasis creates more poverty in a vicious cycle; to combat this neglected disease is to combat inequity.

In Asia and Africa, visceral leishmaniasis is basically anthroponotic, whilst in America and the Mediterranean region, it is a zoonotic disease with dogs as the main reservoir. In 1990, the worldwide incidence was estimated at 500 000 new VL cases annually. These figures were later updated by the WHO, based on a five-year reporting period (2004–2008), with an average of 58 221 new VL cases notified annually, with estimates ranging from 202 100 to 391 400, adjusting for under-reporting. Six countries harboured 90% of the cases: India, Bangladesh, Sudan, South Sudan, Ethiopia and Brazil. A more recent report by the WHO on the 14 high-burden countries (>100 cases per year) shows a decrease of overall cases reported to 30 758 new cases in 2014, with under-reporting estimated as from 1.2-fold to fourfold. This recent decrease is mainly due to a sharp decrease in cases in the South East Asia region, from approximately 50 000 reported cases in 2006 and 2007 to 10 311 cases in 2014. This reduction can be attributed partly to the successful elimination campaign, a possible naturally fluctuating trend of incidence and improvements in living conditions of the local population. Currently, the region with the highest burden worldwide is eastern Africa, with most of the cases observed in Ethiopia, Kenya, Somalia, Sudan, South Sudan and Uganda. The six countries that currently represent 91% of the overall VL burden are India, Ethiopia, Sudan, South Sudan, Somalia and Brazil.

Cutaneous leishmaniasis is reported to be endemic in 98 countries, but 75% of all cases are reported from only ten of these: Afghanistan, Algeria, Brazil, Colombia, Costa Rica, Ethiopia, Iran, Sudan, Peru and Syria. The WHO estimates an incidence of around 0.6–1.2 million new cases per year, although just a fraction of all these numbers are officially reported for a variety of reasons. Unlike the incidence of most other neglected tropical diseases, the incidence of CL is increasing, especially in the last 3–5 years due to migration or displacement of large populations due to crises in the Middle East and North Africa. According to recently published data from the WHO, 12 of the countries with the highest CL prevalence worldwide officially reported 153 027 cases in 2014. In these 12 high-burden countries, the number of cases tripled from over 50 000 in 1998 to over 150 000 in 2005. It was noted, however, by at least one of the 12 countries included in the 2014 report, that there was an underreporting factor of between 2.8 and 4.6.

The real numbers might be even higher if we take into consideration the fact that reporting is problematic in several places, such as refugee camps or in countries where the health care infrastructure has collapsed. In Syria, for example, where millions of people have been internally or externally displaced and many CL cases are occurring among people living in refugee camps. Recent foci have also been described in several countries, including Burkina Faso, Iran, Spain, Argentina and Brazil.

The global mean age-standardized disability-adjusted life years (DALYs; a measure used to calculate the burden of a disease) due to CL has also increased, from 0.29 per 100 000 inhabitants in 1990, to 0.58 in 2013. Nine countries were found to have significantly higher DALYs (per 100 000 inhabitants) compared with the mean: Afghanistan, Sudan, Syria, Yemen, Iraq, Burkina Faso, Bolivia, Haiti and Peru.

In epidemiological terms, regardless of whether the parasite reservoir is human or a non-human sylvatic or domestic mammal, the animal has to fulfil a series of requisites to be considered a primary or secondary reservoir, and this is critical for the control programs: suffering from highly enzootic, chronic infection and proximity to the competent sand fly vector and human. In the case of anthroponotic transmission, prompt diagnosis and treatment are key not only to curing the patient but also to interrupting transmission. In the case of zoonotic transmission, the objective is to reduce the reservoir burden. In both cases, reduction of contact between sand flies, parasite reservoirs and humans will ultimately lead to such a low level of transmission that the cycle stops. In the absence of control programs, the epidemiological incidence of visceral leishmaniasis is recurrent, peaking every 10 years or so, probably when herd immunity is lost. If R0 is greater than 1 in the animal or human reservoir, the disease will reemerge. Although not properly understood and therefore modelled, there are other specific situations in which infected humans may play a role in transmission, basically PKDL, HIV–VL co-infection, and — possibly — asymptomatic carriers.

1.1.1 Post-kala-azar Dermal Leishmaniasis (PKDL)

PKDL is a skin condition that usually develops after treatment of visceral leishmaniasis. PKDL manifests clinically as macular, papular or nodular lesions. PKDL occurs in 1–40% of VL cases, depending on the geographical area. The drug used in the treatment of primary visceral leishmaniasis may be a factor in its incidence, but this is a hypothesis that has not yet been proven. Patients treated with sodium stibogluconate (SSG) seem to be the most prone to developing PKDL, but it occurs at unknown rates after any other medicinal treatment for visceral leishmaniasis. Studies are needed to define PKDL incidence in patients treated with recently introduced new treatment modalities. PKDL patients may infect sandflies, and play a role of pivotal importance in maintaining transmission during inter-epidemic periods. The magnitude of this risk is yet to be estimated via standardized infectivity studies.

1.1.2 Leishmania–HIV Co-infection

Leishmania–HIV co-infection is a growing phenomenon, propelled by the spread of the HIV pandemic to rural areas and the emergence of visceral leishmaniasis in suburban areas. Both HIV and Leishmania not only contribute separately to the impairment of the immune response by targeting the same cells (macrophages), but also exert a synergistic deleterious effect on the host cells, increasing both virus replication and parasite multiplication, and favouring progression of the disease into AIDS. HIV–VL co-infected patients have a higher risk of treatment failure, a higher risk of relapse (especially in those with baseline CD4 counts of less than 100 µl-1 or who do not have an increase in CD4 count during follow-up), and higher rates of mortality. Anti-retroviral therapy and anti-Leishmania secondary prophylaxis should be initiated in this population as soon as possible. Furthermore, the higher number of parasites in peripheral blood in these patients may increase the chances of transmission via sand flies, or when sharing contaminated syringes and could contribute to the spread of drug-resistant strains, especially in anthroponotic visceral leishmaniasis. A total of 35 countries have reported cases of co-infection, with Ethiopia having by far the highest prevalence of HIV–VL worldwide (15–30% of VL cases in certain areas).

1.1.3 Asymptomatic Carriers

The role of asymptomatic carriers in transmission is poorly understood. It has already been determined that large numbers of individuals in endemic areas are infected with Leishmania but do not develop any signs or symptoms of visceral leishmaniasis. The reported ratio of asymptomatic infections to clinical cases of visceral leishmaniasis varies widely, for example, from 4 : 1 in Kenya to 50 : 1 in Spain. Moreover, in 8 out of 316 seropositive carriers in Bihar (2.5%), parasite presence was shown by PCR, meanwhile in Iran PCR positivity was seen in 12.5% of 802 direct agglutination test (DAT)-positives.

A crucial question is whether asymptomatic carriers can infect sand flies and if so, the control measures to be used. At the blood bank of a teaching hospital in Spain, 122 bags from asymptomatic donors were screened. Living parasites were isolated from the buffy coat of 3 of the 30 blood bags that were shown to contain seropositive samples. However, these findings have not been reproduced. Another teaching hospital in Spain tested 483 blood donors and found that 70 (14.5%) samples were positive in a cell proliferation assay (CPA) after in vitro stimulation of peripheral blood mononuclear cells (PBMC) with soluble Leishmania antigen (SLA). Although CPA positivity shows immune reactivity to the parasite, its presence in the blood was transient, as parasites were not detected by quantitative PCR (qPCR) in any case. Moreover, indirect xenodiagnosis was performed in 21 volunteers with negative results. In canine leishmaniasis, it has been shown using xenodiagnosis that up to 50% of naturally-infected asymptomatic dogs can transmit Leishmania to sand flies. Extrapolating these results in canine leishmaniasis to asymptomatic humans may be too risky, given what is currently known, and it is better not to speculate on the target product profile (TPP) for a drug to be used in this group of subjects; more research is needed before embarking on drug development. Today, the only good reason to put an asymptomatic carrier onto preventive chemotherapy with conventional medicines is if he or she has to be immunosuppressed for medical indications, i.e. transplantation.

(Continues...)

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Dettagli dell'edizione

• Editore: Royal Society of Chemistry
• Data di pubblicazione: 2017
• Lingua: Inglese
• ISBN 10: 1782628894
• ISBN 13: 9781782628897
• Rilegatura: Copertina rigida
• Numero edizione: 1
• Numero di pagine: 402
• Redattore: Rivas Luis, Gil Carmen
• Contatto del produttore: non disponibile
• Persona responsabile: GPSR Kontakt; gpsr@libri.de; ; Europaallee 1; Bad Hersfeld; 36244; Germania