Neglected Tropical Diseases

Drug Discovery and Development

David C. Swinney, Michael P. Pollastri, David C. Swinney, Michael P. Pollastri, Raimund Mannhold, Helmut Buschmann, Jörg Holenz

• Publisher: Wiley-VCH
• Year: 2019
• Print ISBN: 9783527343041
• eBook ISBN: 9783527808649
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

A drug discovery reference to the crippling tropical diseases that affect more than 1 billion people.

Neglected Tropical Diseases is the first book of its kind to offer a guide that follows the World Health Organization?s list of neglected tropical diseases. The authors?all are experts on the topic?address the development of effective treatments for 12 crippling infectious diseases that affect almost 20% of the world?s popluation.

The book includes information on the common approaches and the most important factors that lead to the development of new drugs for treating tropical diseases. Individual chapters review 12 neglected tropical diseases that are grouped by infectious agent, from viruses to bacteria to eukaryotic parasites. For each of these diseases, the book explains the unmet medical need and explores the current and potential drug discovery strategies. The book also includes information on potential drug compounds derived from natural products. This important book:

-Ties together information from different sources for developing novel treatsments forneglected tropical diseases
-Is aligned with WHO?s initiative to eradicate tropical diseases
-Outlines current and potential drugs for treating tropical diseases
-Provides a standard reference for the entire field

Written for medicinal chemists, pharmaceutical chemists, pharmaceutical industry, virologists, parasitologists, and specialists on tropics medicine, Neglected Tropical Diseases offers an essential guide and a systematic reference for the development of successful treatments for 12 crippling infectious diseases.

1
Drug Discovery Strategies for Neglected Tropical Diseases: Repurposing Knowledge, Mechanisms and Therapeutics to Increase Discovery Efficiency

David C. Swinney¹, and Michael P. Pollastri²

¹DCSwinney Consulting, Belmont, CA, 94002, USA

²Northeastern University, Department of Chemistry & Chemical Biology, 360 Huntington Avenue, Boston, MA 02115, USA

1.1 Introduction

Neglected tropical diseases (NTDs) are a diverse group of communicable diseases that prevail in tropical and subtropical conditions in 149 countries. These diseases include infections by bacteria, protozoans, helminths, and viruses. Analyses have estimated that NTDs affect more than one billion people and cost developing economies billions of dollars every year [1,2]. Populations living in poverty, without adequate sanitation, and in close contact with infectious vectors and domestic animals and livestock are those worst affected. We refer readers to the websites of the WHO and CDC for more specifics on the individual diseases [3,4].

Six of the infections caused by NTDs (dracunculiasis, lymphatic filariasis, onchocerciasis, schistosomiasis, soil‐transmitted helminths, and trachoma) can be controlled or even eliminated through mass administration of safe and effective medicines (mass drug administration, MDA), or other, effective interventions. Along with therapeutic interventions, efforts to control the vectors (e.g. mosquitoes, black flies) that transmit these diseases and to improve basic water, sanitation, and hygiene are highly effective strategies against these NTDs [4].

There are still many NTDs that cannot be controlled, due to their mechanism of transmission, or their presence in zoonotic reservoirs, among other reasons. Thus, there is a need for new affordable, effective therapeutics in addition to the plans to control the disease vectors and improve basic water, sanitation, and hygiene.

1.2 First‐line Therapies for NTDs and Mechanisms of Action

Most medicines currently used to treat NTDs were discovered many decades ago, despite having limitations (Table 1.1). For example, suramin used for the treatment of human African trypanosomiasis (HAT) was discovered almost 100 years ago and is still used, albeit a number of newer medicines are now available [5,6]. Strikingly, most NTD medicines were discovered prior to the 1990s, when molecular biology, molecular genetics, and associated technologies became central to medicine and drug discovery.

Table 1.1 First‐line therapies for NTDs and how they were discovered.

First‐line	Diseases	Mechanism	Year
Albendazole	Ascariasis, hookworm, echinococcosis, lymphatic filariasis	Tubulin inhibitor	1987
Ivermectin	Lymphatic filariasis, onchocerciasis	Ion channel	1981
Praziquantel	Schistosomiasis, foodborne trematodiasis, Taencasis/cysticerosis	Membrane disruption	1982
Benznidazole	Trichuriasis, chagas	Free radical toxicity	1966
Nifurtimox	Chagas, HAT	Oxidative stress	1970
Pentamidine	HAT	Cross‐link DNA	1937
Suramin	HAT	Disrupt energy metabolism	1920
Melarsoprol	HAT	Trypanothione and pyruvate kinase inhibition	1949
Eflornithine	HAT	Ornithine decarboxylase inhibitor	1990
Amphotericin B	Leishmaniasis	Membrane disruption	1953
Miltefosine	Leishmaniasis	Membrane disruption	2002
Rifampicin	Buruli ulcer, leprosy	RNA polymerase	1971
Streptomycin	Buruli ulcer	Protein synthesis inhibition	1943
Dapsone	Leprosy	Dihydropteroate synthase inhibitor	1937
Clofazimine	Leprosy	DNA chelator	1969
Azithromycin	Trachoma, YAWS	Protein synthesis inhibition	1988
Triclabendazole	Foodborne trematodiasis, fascioliasis	Tubulin inhibitor	1989
Niclosamide	Taencasis/cysticerosis	Disrupt energy metabolism	1960s

The mechanisms of action of these medicines involve disruption of processes essential to an organism's survival. These actions include disruption of microtubules (albendazole, triclabendazole) [7], ion flux (ivermectin) [8], oxidative stress (benznidazole, nifurtimox) [6,9], disruption of energy production (suramin, niclosamide) [10], inhibition of protein synthesis (streptomycin and azithromycin) [11], inhibition of RNA synthesis (rifampicin) [12], disruption of membrane integrity (praziquantel [13,14], amphotericin B [15], miltefosine [16,17], clofazimine [18]), and inhibition of production of essential metabolites (eflornithine, dapsone) [5,19].

Most of these functions are not unique to the infectious agents. Selectivity over human homologs is required to achieve a useful safety profile. Differences in binding affinity between the microbe and human homologs provide the selectivity for some (albendazole, ivermectin), but not all, of the medicines. Perhaps, most interesting is that for some of the therapeutics, selectivity is thought to be achieved by the existence of compensatory mechanisms in humans. Greater free radical quenching in human cells versus parasite contribute the selectivity for benznidazole and nifurtimox [15]. Alternative uptake mechanisms for folic acid in hosts contribute to safety of dapsone [19]. Other exploitable differences include compound disposition (e.g. high‐affinity uptake systems in trypanosomes by pentamidine) [6], and composition of membranes, which is a key selectivity feature for the function of amphotericin B [15].

1.3 Drug Discovery Efficiency

Drug discovery is an endeavor with very high attrition rates [20]. The high attrition rates are particularly detrimental for drug discovery for NTDs, owing to the disproportionately low research investment in this activity. As such, processes need to be employed to reduce the risk of attrition. Two important aspects relevant to medicinal chemistry are the strategies that provide therapeutic candidates and the critical componen...

Table of contents

• Cover
• Table of Contents
• A Personal Foreword
• Preface
• 1 Drug Discovery Strategies for Neglected Tropical Diseases: Repurposing Knowledge, Mechanisms and Therapeutics to Increase Discovery Efficiency
• Part I: Virus
• Part II: Kinetoplastids
• Part III: Helminths
• Part IV: Bacteria
• Index
• End User License Agreement