Drug discovery for leishmaniasis

422 Pages·2018·8.223 MB·English

by  Luis Rivas, Luis Rivas, Carmen Gil, Carmen Gil, David Thurston, Ana Martinez, Philippe Desjeux, Jorge Alvar, Charles Mowdray, Fabiana Alves, Vanessa Yardley, Julio Martin, Christopher Fernandez, Nuria Campillo, Joao Henrique G Lago, Cynthia Demicheli, Katharine Carter, Miguel Angel Morales, Dan Zilberstein, Paul A Michels, Ana Tomas, Rafael Balaña, Louis Maes, Albert Descoteaux

Drug Discovery for Leishmaniasis
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Drug Discovery Series
Editor-in-Chief:
David Thurston, King’s College, UK
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P Series Editors:
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77- David Fox, Vulpine Science and Learning, UK
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10 Ana Martinez, Centro de Investigaciones Biolo´gicas-CSIC, Spain
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88 David Rotella, Montclair State University, USA
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81 Sarah Skerratt, Vertex Pharmaceuticals, UK
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03 Editorial Advisor:
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10. Hong Shen, Roche Innovation Center Shanghai, China
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g | Titles in the Series:
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c. 1: Metabolism, Pharmacokinetics and Toxicity of Functional Groups
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bs.r 2: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1
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http://p 34:: EAmcceorugnintsgiDnrDurgusganDdiscToavregreyts for Alzheimer’s Disease; Volume 2
n 5: New Frontiers in Chemical Biology
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17 6: Animal Models for Neurodegenerative Disease
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er 2 7: Neurodegeneration
ob 8: G Protein-Coupled Receptors
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. n 2 10: Extracellular and Intracellular Signaling
d o 11: New Synthetic Technologies in Medicinal Chemistry
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h 12: New Horizons in Predictive Toxicology
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14: Neglected Diseases and Drug Discovery
15: Biomedical Imaging
16: Pharmaceutical Salts and Cocrystals
17: Polyamine Drug Discovery
18: Proteinases as Drug Targets
19: Kinase Drug Discovery
20: Drug Design Strategies: Computational Techniques and Applications
21: Designing Multi-Target Drugs
22: Nanostructured Biomaterials for Overcoming Biological Barriers
23: Physico-Chemical and Computational Approaches to Drug Discovery
24: Biomarkers for Traumatic Brain Injury
25: Drug Discovery from Natural Products
26: Anti-Inflammatory Drug Discovery
27: New Therapeutic Strategies for Type 2 Diabetes: Small Molecules
28: Drug Discovery for Psychiatric Disorders
29: Organic Chemistry of Drug Degradation
30: Computational Approaches to Nuclear Receptors
31: Traditional Chinese Medicine
32: Successful Strategies for the Discovery of Antiviral Drugs
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33: Comprehensive Biomarker Discovery and Validation for
Clinical Application
34: Emerging Drugs and Targets for Parkinson’s Disease
35: Pain Therapeutics; Current and Future Treatment Paradigms
1 36: Biotherapeutics: Recent Developments using Chemical and
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P0 Molecular Biology
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7- 37: Inhibitors of Molecular Chaperones as Therapeutic Agents
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01 38: Orphan Drugs and Rare Diseases
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80 39: Ion Channel Drug Discovery
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17 40: Macrocycles in Drug Discovery
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97 41: Human-based Systems for Translational Research
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3 42: Venoms to Drugs: Venom as a Source for the Development of
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0. Human Therapeutics
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oi: 43: Carbohydrates in Drug Design and Discovery
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c.or 45: Cardiovascular and Metabolic Disease: Scientific Discoveries and
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s.r New Therapies
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u 46: Green Chemistry Strategies for Drug Discovery
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p:// 47: Fragment-Based Drug Discovery
n htt 48: Epigenetics for Drug Discovery
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7 49: New Horizons in Predictive Drug Metabolism and Pharmacokinetics
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20 50: Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis,
ber Evaluation
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ct 51: Nanomedicines: Design, Delivery and Detection
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6 52: Synthetic Methods in Drug Discovery: Volume 1
. on 2 53: Synthetic Methods in Drug Discovery: Volume 2
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e 54: Drug Transporters: Role and Importance in ADME and
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P 55: Drug Transporters: Recent Advances and Emerging Technologies
56: Allosterism in Drug Discovery
57: Anti-aging Drugs: From Basic Research to Clinical Practice
58: Antibiotic Drug Discovery: New Targets and Molecular Entities
59: Peptide-based Drug Discovery: Challenges and New Therapeutics
60: Drug Discovery for Leishmaniasis
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Drug Discovery for
Leishmaniasis
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01 Edited by
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7 Luis Rivas
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3 Centro de Investigaciones Biolo´gicas, Madrid, Spain
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pu Centro de Investigaciones Biolo´gicas, Madrid, Spain
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39/ DrugDiscoverySeriesNo.60
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doi:1 PPrDinFteIISSBBNN::997788--11--7788286021--808197--77
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c.or ISSN:2041-3203
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77- Foreword
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1 This book has been produced to provide to the reader with an integral and
doi: updated approach to the chemotherapy of leishmaniasis. Aside from the
org | partialsuccessofreservoirandvectorcontrol,aswellaspromisingadvances
sc. in vaccine development against human and canine leishmaniasis, chemo-
bs.r therapy is nowadays the workhorse to fight this disease.
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p://p To fulfill this goal, the book is structured as 19 chapters grouped
htt under three major topics: general aspects of leishmaniasis, the role of
n medicinal chemistry in Leishmania pharmacology and the description of
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17 some appealing targets to define new therapeutic candidates.
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er 2 The first topic provides an actual assessment of leishmaniasis and its
ob chemotherapy. J. Alvar and B. Arana describe the current situation of
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O leishmaniasis and its impact on human health (Chapter 1). The next two
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. n 2 chapters tackle the current strategies on chemotherapy, including new
d o candidates under clinical trial (C. E. Mowbray), and how miltefosine was
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sh implemented as a first-line leishmanicidal drug (F. Alves et al.).
ubli The second thematic block focuses on medicinal chemistry efforts in the
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quest for new leishmanicidal drugs. To this end, this part starts with the
description of the different drug assays used to test leishmanicidal drugs
(V.YardleyandM.Konordiu),andtheprocessofhigh-throughputscreening
(J. Martin et al.) to define new candidates from chemical libraries. The
growing importance of ‘‘omics’’ (C. Fern´andez-Prada et al.) and in silico
technologies(C.Rocaetal.)foruncoveringnewdrugcandidatesensues.The
next three chapters describe the current scaffolds for dug development
obtained either from chemical synthesis (A. Mart´ınez and C. Gil), or
from natural products (J. H. G. Lago and A. G. Tempone), as well as the
renaissance of organo-metallic compounds which overcome previous
pharmacological hurdles of current antimonials (B. Rodrigues do Prado
et al.). This part finishes with a description of the different approaches for
DrugDiscoverySeriesNo.60
DrugDiscoveryforLeishmaniasis
EditedbyLuisRivasandCarmenGil
rTheRoyalSocietyofChemistry2018
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
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viii Foreword
drug delivery (K. C. Carter and A. B. Mullen), essential for yielding an
improved chemotherapeutical outcome.
The final section of the book describes the differential targets that are
or can be exploited in the development of new leishmanicidal drugs.
7 These targets include the nucleic acids and their associated biological
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P0 processes (B. Norris-Mullins and M. A. Morales), the phospholipid matrix
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7- (L.Rivasetal.),nutrienttransporters(D.Zilberstein),carbon(H.Acostaetal.)
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01 and redox metabolism (H. Castro et al.). Chapter 17 (R. M. Reguera et al.),
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80 describesarepresentativeexampleofadrugdevelopmentprogrammebased
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17 onadefinedtarget:thetopoisomerases.Finally,twoimportantaspectswitha
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97 relevant influence on the final result of leishmanicidal therapies are drug
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3 resistance and the interphase parasite-macrophage, which are described in
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0. the chapterswritten by A. Mondelaers etal. and A. Descoteaux respectively.
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oi: Inall, thishighlyrelevantandtimely book emphasizesnotonlythegreat
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g | progresses achieved so far but also the crucial need for future discovery of
or new drug candidates and future development of new leishmanicidal drugs.
c.
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s.r Inviewofthehighcostandthelongperiodoftimeneededfordeveloping
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u a new drug, the book conveys a clear and urgent message to health
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p:// authoritiesaroundtheworld:itisanabsoluteprioritytomakeeveryeffortto
n htt protect the drugs currently in use, to prevent, by all available means, the
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7 appearanceofresistance(e.g.strictuseofthedrugsattherightdoseandthe
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20 righttime,useofcombinationtherapywhenrelevantandfeasible,etc.)and
er to put in place a strong pharmaco-vigilance program at national level to
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6 This useful book deserves to be made widely available and adopted and
. on 2 used worldwide.
d
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bli Philippe Desjeux
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P Former chief of leishmaniasis control at WHO HQ and former leishmaniasis
coordinator at TDR, Geneva, Switzerland. Former senior program officer at
iOWH and PATH, grantees of the B & M Gates Foundation.
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03 I. Appraisal of Leishmaniasis Chemotherapy,
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10. Current Status and Pipeline Strategies
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c.or Jorge Alvar and Byron Arana
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blis Unmet Needs 16
Pu 1.3.1 Visceral Leishmaniasis 16
1.3.2 Cutaneous Leishmaniasis 18
1.3.3 Drug Access 19
1.4 Conclusion. Development of an Elimination Tool 20
References 21
Chapter 2 Anti-leishmanial Drug Discovery: Past, Present and
Future Perspectives 24
Charles E. Mowbray
2.1 Introduction 24
DrugDiscoverySeriesNo.60
DrugDiscoveryforLeishmaniasis
EditedbyLuisRivasandCarmenGil
rTheRoyalSocietyofChemistry2018
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
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x Contents
2.2 Current Drugs for Leishmaniasis 25
2.2.1 Lessons Learned from the Properties
of Current Drugs for Leishmaniasis 27
2.3 Medicinal Chemistry Challenges and Strategies
09 to Discover New Anti-leishmanial Drugs 27
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0. Chapter3 FromBenchtoBedside:DevelopmentandOptimizationof
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g | Fabiana Alves, Jean-Yves Gillon, Byron Arana and
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sc. Thomas P. C. Dorlo
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htt 3.2 The Role of Preclinical Models in Preclinical to
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. on 2 Preclinical Models 40
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3.3 Challenges and Opportunities to Optimize
Therapies for Leishmaniasis: The Case of
Miltefosine 42
3.3.1 Discovery and Development History
of Miltefosine for Leishmaniasis 42
3.3.2 Changing Patterns in Clinical
Efficacy 43
3.3.3 Dose Optimization of Miltefosine for
Future Combination Strategies 46
3.3.4 Translational Approach to Manage
Miltefosine’s Main Safety Concern:
Teratogenicity 49
3.4 Final Remarks 50
Acknowledgements 50
References 51