Editorial pubs.acs.org/CR
Introduction: Drug Discovery and Development for Neglected Diseases
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While no drug company is prepared to support an entire pipeline from discovery to clinical trials, several companies have invested resources and labor to aid in overcoming bottlenecks for at least a few of these diseases. For example, GlaxoSmithKline (GSK) maintains a cadre of chemists and biologists at the Tres Cantos Facility in Spain that has carried out both screening and medicinal chemistry optimization, particularly for diseases such as malaria. Several currently used antiparasitic drugs have had their origin in veterinary medicine. Merck has provided Ivermectin, the current therapy for onchocerciasis (river blindness), as a spin-off of the use of this drug for veterinary purposes. This “repurposing” of drugs from veterinary use remains a potential pipeline to new human antiparasitic agents, since veterinary medicine remains an important commercial venture for companies. Paula Gomes and coauthors focused on “recycling” or “repurposing” currently approved drugs for the treatment of malaria. Other approaches to discovery and development of drugs targeting malaria can be found in the Review by David Barnett and Kip Guy. Medicinal chemistry approaches to drug development are highlighted in the Review by William Roush, Larissa Podust, and Jun Yong Choi, who have taken the classic structure-based approach to optimize leads targeting the CYP51 enzyme in Trypanosoma cruzi. There are a number of reasons why pharmaceutical companies have donated time, effort, and compound libraries to groups attempting to develop antiparasitic drugs. In some cases, this is done for good publicity, in some cases to highlight social responsibility, and in other cases because of prodding from international organizations such as the Bill and Melinda Gates Foundation. In the past five years, as more companies have indicated a willingness to donate resources, organizations such as WIPO (World Intellectual Property Organization) and Bioventures for Global Health (BVGH) have emerged to broker collaborations between industry and academic, nonprofit, or government groups attempting to follow the drug discovery and development pipeline. Jennifer Dent, Roopa Ramamoorthi, and coauthors give details on how WIPO catalyzed collaborations between the pharmaceutical industry and the nonprofit sector can take advantage of compound libraries developed in industry to target neglected tropical diseases.
eglected tropical diseases (NTDs) refer to a group of global health problems primarily caused by parasitic organisms (Table 1). Parasites are eukaryotic organisms that range from singe-cell primitive protozoa to complex multicellular worms or helminths. The term “parasite” derives from classical Greek definitions that include “a guest who comes to dinner and doesn’t leave” or “the name of a class of priests who had meals at public expense”. While seemingly exotic, parasitic diseases affect hundreds of millions of people worldwide (Table 1). However, there has been little interest in the pharmaceutical industry in discovering and developing new drugs for these diseases because they do not represent viable economic entities. These diseases are termed “neglected” because they primarily affect poor people in poor regions of the world. This is not to say that pharmaceutical companies have completely ignored the problem of effective and safe therapy, as will be discussed in this issue. Nevertheless, the lack of any potential for a “blockbuster drug” has resulted in major challenges to government, academic, and nonprofit agencies dedicated to the discovery, development, and launch of new therapy for NTDs. The drug “pipeline”, as envisioned by the pharmaceutical industry, remains largely unfilled for each of these diseases (Table 2). The first step in this process, targeting family selection, has traditionally been done at academic centers. Fortunately, academic interest in the biology of the host/parasite relationship has led to decades of research on the biochemical pathways of parasites, including modes of entry into the host, metabolism of host proteins, salvaging of metabolic building blocks, and evasion of the host immune response. As a result, the road to anti-parasitic drug development begins at a very different place than that for most other diseases. Even before the recent genome revolution, many molecular targets had been identified and validated, or eliminated. A good place to start in this Thematic Issue is the Review by Kelly Chibale et al. on recent approaches to chemical discovery and development against neglected tropical diseases. This review provides the reader with a background on malaria and schistosomiasis as well as highlighting several general approaches to drug development targeting other neglected tropical diseases.
WHAT ARE THE PRESENT ROADBLOCKS OR BOTTLENECKS FOR DRUG DEVELOPMENT TARGETING NEGLECTED TROPICAL DISEASES? As in any drug development effort, medicinal chemistry plays a key role in hit-to-lead success, as well as in lead optimization to produce a viable clinical candidate. The appalling lack of a medicinal chemistry labor force in this field is the most relevant shortcoming that has resulted from the lack of industry interest. Therefore, the Reviews in this Thematic Issue, outlining the efforts of medicinal chemists worldwide to address these issues, represent an important foundation for future success in developing new drugs targeting these diseases. © 2014 American Chemical Society
WHAT IS MISSING IN THE DRUG DEVELOPMENT PIPELINE FOR NEGLECTED TROPICAL DISEASES? One element that is not missing is high-throughput screening. There are now many screening centers worldwide. These range from contractual collaborations fostered by international Special Issue: 2014 Drug Discovery and Development for Neglected Diseases Published: November 26, 2014 11131
dx.doi.org/10.1021/cr500546h | Chem. Rev. 2014, 114, 11131−11137
Chemical Reviews
Editorial
Table 1. Major Neglected Tropical Disease (NTD) Burden and Current Drug Therapies Disease
Number of cases worldwide (millions)a
Causative Agent
Human African trypanosomiasis (HAT)
Leishmaniasis
Chagas Disease Malaria Schistosomiasis
Trypanosoma brucei gambiense (98% of cases) Trypanosoma brucei rhodesiense (2% of cases) Various Leishmania species Cutaneous: L. major, L. tropica, L. aethiopica, L. brasiliensis, L. mexicana Muco-cutaneous: L. brasiliensis, L anazonensis, L. panamensis, L. guyanensis Visceral: L. donovani, L infantum Trypanosoma cruzi Several species of Plasmodium; P. falciparum is most dangerous Schistosoma mansoni, Schistosoma hematobium, Schistosoma japonicum
Annual deaths worldwide (thousands)b
0.3
Daily life-adjusted years (DALYs) lost annually (thousands)c
Current Drug Therapies
53
560
Pentamidine, Suramin, Melarsoprol
12
46
3,317
Pentavalent antimonials, Amphotercin B, Miltefosine, Paromomycin
7−8 219
11 839
546 82,685
243
39
3,309
Benznidazole, Nifurtimox Chloroquine, Artemisin-based combination therapies Praziquantel
a
Source: World Health Organization.1−5 bSource: World Health Organization6 doi: 10.1371/journal.pntd.0000114.t003. cSource: World Health Organization7 doi: 10.1016/S0140-6736(12)61766-8.
Table 2. Disease Burden and Number of Developed Drug Products and New Chemical Entities (NCEs) for Major Diseases from 2000−2011 Disease
Daily life-adjusted years (DALYs) lost annually (thousands)a
All new productsb
NCEs onlyb
b,c
Neuropsychiatric diseases
199,280 (13%)
Neglected diseases Diarrhceal diseases Malaria Tuberculosis Neglected tropical diseases Leishmaniasis Schistosomiasis Human African trypanosomiasis (HAT) Chagas Disease Other neglected diseases
159,976 72,777 33,976 34,217 18,325 1,974 1,707 1,673
Cardiovascular diseases
151,377 (10%)
70 (8%)
29 (9%)
20010 (13%)
Cancer
79,765 (5%)
103 (12%)
81 (24%)
31087 (20%)
Respiratory diseases (noninfectious)
59,039 (4%)
31 (4%)
7 (2%)
HIV/AIDS
58,513 (4%)
36 (4%)
12 (4%)
4137 (3%)
Diabetes mellitus
19,705 (1%)
28 (3%)
9 (3%)
7839 (5%)
All other diseases
795,604 (52%)
401 (47%)
145 (43%)
83356 (56%)
1,523,259 (100%)
850 (100%)
336 (100%)
148,445 (100%)
Total
134 (16%)
Number of clinical trials (2000−2011)
(11%) (5%) (2%) (2%) (1%)
37 7 12 7 5 3 0 1
430 681 (
