Novel Therapeutic Approaches for Neglected Infectious Diseases

Neglected infectious diseases are broadly understood as those communicable diseases affecting populations mainly in low-income countries. They are a leading cause of mortality and chronic disability. Among them, neglected tropical diseases (NTDs) are a group of infectious diseases categorized by the particular neglect they have suffered in terms of investment in control measures, compared with malaria and tuberculosis, “the big two” within the neglected diseases.

Of the 850 new therapeutic products registered in 2000–2011, only 5 (0.6%) were indicated for NTDs, none of them being a new chemical entity (NCE) or vaccine. ¹ However, the global disease burden caused by NTDs is high. According to the World Health Organization (WHO), the number of disability-adjusted life-years (DALYs) caused by NTDs in 2004 was 18,325, ¹ just half of the figure for malaria or tuberculosis and similar to that of diabetes mellitus. The lack of investment in drug discovery for NTDs has been partially due to the absence of economic incentives. The issue of poverty is central to the nature of NTDs, both as a major cause for the diseases and also aggravating the socioeconomic condition of the affected populations. ²

The NTDs encompass a broad range of viral, bacterial, and parasitic infections. There are 17 core NTDs as defined by WHO. ³ The control of these diseases is overseen by the Control of Neglected Tropical Diseases program at WHO. NTDs have been categorized as either “tool ready,” given that there are tools (e.g., drugs) that can be implemented now, or “tool deficient” because many of these tools (e.g., drugs and diagnostics) and implementation strategies are inadequate to achieve the desired goals. ³ New effective, safe, and affordable drugs, adapted to the field and therefore preferably oral, are needed. Indeed, more than one new drug for each disease is desirable, so that combination therapy can be envisaged to improve efficacy and avoid drug resistance and to provide backup drugs when resistance emerges. To address this unmet need, the pharmaceutical industry, public institutions, and foundations have recently started to join efforts. The goal of these public-private partnerships is to discover and develop novel treatments in NTDs in fulfillment of their commitment to global health.

In January 2012, WHO, the Bill & Melinda Gates Foundation (B&MGF), political representatives of several member states, and CEOs from the pharmaceutical industry published a roadmap known as the London Declaration on Neglected Tropical Diseases. They pledged to (a) sustain, expand, and extend the drug supply; (b) accelerate research and development for new treatments; and (c) increase funding to improve implementation to control or eliminate 10 NTDs. ⁴

Accelerating R&D for new treatments in NTDs has encountered several fundamental barriers. The complex biology of many of these parasites and their need for vectors for development and transmission challenge the traditional industrial-scale drug discovery programs. The general neglect that these diseases have encountered has meant that basic research findings have not found their way into a drug discovery pipeline. Despite the basic research conducted on the biology of these organisms, the paucity of validated molecular targets and the lack of assays that recapitulate relevant biology of the parasites and are amenable to high-throughput screening (HTS) platforms has hindered the ability to evaluate large sets of compounds with lead-like properties in the pursuit of promising drug discovery starting points.

Although target-based chemotherapeutic screens have been a focus of drug discovery programs in the postgenomic era, there has been a movement toward returning to phenotypic-based whole-organism screening assays.^5,6 Target-based approaches, perhaps with the exception of Trypanosoma brucei, have been hampered by the lack of genetic tools to validate drug targets in these parasites. Thus, running a target-agnostic phenotypic assay upfront in primary screening is a sensible and valid approach to early drug discovery. Furthermore, compounds identified from phenotypic screens can also serve as chemical-biology probes for the identification and validation of new tractable targets.

Moreover, significant differences may exist in drug sensitivity between different life cycle stages, and thus the choice of the most disease-relevant in vitro assay is key to success in translating compound activity from in vitro to in vivo and eventually to the clinic. As an example, whereas the extracellular bloodstream trypomastigote form of T. brucei is the relevant stage for drug discovery in sleeping sickness, the intracellular amastigotes of Leishmania donovani and Trypanosoma cruzi in the host cells of infected tissues are the discovery focus for visceral leishmaniasis and Chagas disease. In recent years, there have been significant advances in automated microscopy that enable compound testing against intracellular parasites in high-throughput mode.^7–13

Under these circumstances and on behalf of the Journal of Biomolecular Screening (JBS), we are very pleased to introduce this special issue dedicated specifically to Novel Therapeutic Approaches for Neglected Infectious Diseases. This issue is a very short summary of the current status of the discovery efforts to find new drugs for these diseases. We hope it covers a sufficiently broad range of aspects in the field to give an idea of the complexity and challenges of the diseases themselves but also of the scientific environment surrounding these diseases. The field of drug discovery for NTDs has indeed changed dramatically during the past 10 years; it not only now applies the most modern technologies to find new chemistry starting points, tackle translational challenges, and look for new diagnostic tools but also has led to new paradigms and collaboration efforts (product development partnerships or PDPs, open access, open-source drug discovery).

Although neglected infectious diseases are very complex and varied, involving protozoan parasites (sleeping sickness, leishmaniasis, Chagas disease), worms (schistosomiasis, filariasis, onchocerciasis), or viruses (dengue, Rift valley), technologies and approaches are now being applied to discover and develop new drugs, which hardly differ from those used in other human and infectious diseases (see examples for Chagas disease drug discovery^14,15 and for onchocerciasis and lymphatic filariasis ¹⁶ ). For instance, metabolomics ¹⁷ are being implemented to identify pathways and targets for given compounds that were identified through phenotypic screens. Yeast technology also has proven to be amenable to the HTS molecular targets from parasites in a cellular milieu. ¹⁸ Bioluminescent live-imaging technique allows one to observe infection caused by genetically modified parasites and the effect of drugs on the course of the infection. ¹⁹ Orthology and target-based screen approaches are again on the rise with the advent and validation of new targets allowing technologies such as fragment-based drug design or structure-based drug discovery to be applied to the search of new drugs for NTDs.^20–24

New technologies have been applied to implement phenotypic screening assays in high-throughput mode^15,25,26 or to develop secondary assays that allow researchers to interrogate the mode of action and susceptibility of new agents. ²⁷ Modern techniques are also revolutionizing the way parasitic infections are diagnosed and parasite burden is measured. ²⁸

However, pragmatic approaches such as drug repurposing and open access also are examined. Other approaches, such as the screening of natural products and extracts in big scale, are currently a new avenue to look at more diversity in the chemical space for these diseases. ²⁹

Protozoan parasites have developed sophisticated mechanisms to elude the defense response of the host. Some are able to live intracellularly in immune cells by hijacking important components of response. Thus, host-pathogen interactions should not be overlooked when investigating the potential of new drugs.

In summary, despite the huge unmet medical need, there are few effective and safe drug treatments against these parasites, and new therapeutic approaches should be urgently developed. Furthermore, it has not been until recently that modern technologies in drug discovery commonly applied to other therapeutic areas have started to be implemented in parasitology research. Hopefully, we are living the advent of a new era in which open innovation and public-private partnership will fill the gap existing between basic research and medicine in this field. At the end of the day, the goal is not only that these diseases are not neglected any longer but that society does not neglect the people suffering from them. Achieving this goal is a shared responsibility, and the success will depend on everyone’s contribution. We expect that this issue modestly will contribute to strengthen the links and shorten the distance between parasitology research and drug discovery.

Finally, we would like to thank all the authors and peer reviewers who revised and contributed to improve the quality of the manuscripts.

We hope readers will enjoy the reading of this special issue and realize that drug discovery for NTDs is currently going through very exciting developments.

Eric Chatelain, PhDDrugs for Neglected Disease initiative (DNDi)Geneva, Switzerland Julio Martin-Plaza, PhD GlaxoSmithKlineTres Cantos, Spain