Current Topics in Medicinal Chemistry - Volume 11, Issue 10, 2011

Half the disease burden of the developing world - 80% of the world's population - is due to infectious diseases, with one billion people suffering from a neglected tropical disease. Constant vigilance is needed against ancient killers such as malaria and tuberculosis as new drugs can lose their effect quickly due to the spread of drug resistance. Yet despite these levels of disease burden, between 1975 and 1999 only thirteen new drugs were approved that targeted diseases of the developing world. However, over the past decade the tide has began to turn, in both recognising the paucity of new medicines dedicated to the diseases of the most neglected populations and in initiating efforts to redress the problem. In recent years there has been a remarkable emergence of drug discovery efforts towards the infectious diseases of the developing world. The challenges of neglected disease drug discovery are two-fold: firstly the scientific challenge of identifying clinical drug candidates that fulfil the challenging ‘product profiles’ required for tropical diseases, where cost-of-goods, safety and drug resistance are essential consideration as the patient population are often children and women of child-baring age. Secondly, the economic challenge of the conducting modern drug discovery within the constrained resources of charity and government funding. This edition of Current Topics in Medicinal Chemistry is dedicated to the theme of “Progress in Neglected Disease Drug Discovery”. The edition can be considered in two parts. The first half of the edition is dedicated to progress to date in the medicinal chemistry of three major neglected infectious disease areas: tuberculosis, malaria and trypanosomiasis. The second half of the edition is devoted to issues of target validation and lead identification, which are crucial in ensuring a robust pipeline of drug candidates are developed on the resources available. We would sincerely like to thank of the authors of these six articles, many of whom are highly respected leaders in their fields, for not only their contributions to this special edition but for dedicating their careers to advancing medicines for the poorest people on the planet. We hope many readers will be inspired by the advances in the field to make their own contributions to the challenge the world faces from the neglected infectious diseases.

Despite massive global efforts tuberculosis rates continue to climb and drug-resistance rates are rising to alarming levels. Discovering new agents for treating this bacterial pathogen poses unique challenges, but these challenges have been faced throughout the entire modern history of research into anti-infectives. This review looks back at every decade since the 1940s and summarizes the most important drugs developed during each decade highlighting the lessons learned during these successful medicinal chemistry programs. Looking forward we must accelerate the integration of these past lessons with the impressive advances that have been made in the basic understanding of the biology of this disease.

Malaria is one of the most prevalent and devastating infectious diseases of our time. Yet, unfortunately, apart from artemisinin combination therapies there are relatively few effective treatments for Plasmodium falciparum and only one treatment for the radical cure of Plasmodium vivax. Novel classes of antimalarial medicines are urgently needed given the long-term inevitability of resistance to current therapies and the need for drugs that are well tolerated by all. This review summarises the antimalarials developed and registered thus far, as well as describing some of the new small molecule therapy approaches being developed as a contribution towards the malaria eradication agenda.

African sleeping sickness is endemic in sub-Saharan Africa where the WHO estimates that 60 million people are at risk for the disease. Human African trypanosomiasis (HAT) is 100% fatal if untreated and the current drug therapies have significant limitations due to toxicity and difficult treatment regimes. No new chemical agents have been approved since eflornithine in 1990. The pentamidine analog DB289, which was in late stage clinical trials for the treatment of early stage HAT recently failed due to toxicity issues. A new protocol for the treatment of late-stage T. brucei gambiense that uses combination nifurtomox/eflornithine (NECT) was recently shown to have better safety and efficacy than eflornithine alone, while being easier to administer. This breakthrough represents the only new therapy for HAT since the approval of eflornithine. A number of research programs are on going to exploit the unusual biochemical pathways in the parasite to identify new targets for target based drug discovery programs. HTS efforts are also underway to discover new chemical entities through whole organism screening approaches. A number of inhibitors with anti-trypanosomal activity have been identified by both approaches, but none of the programs are yet at the stage of identifying a preclinical candidate. This dire situation underscores the need for continued effort to identify new chemical agents for the treatment of HAT.

The discovery of drugs is a lengthy, high-risk and expensive business taking at least 12 years and is estimated to cost upwards of US$800 million for each drug to be successfully approved for clinical use. Much of this cost is driven by the late phase clinical trials and therefore the ability to terminate early those projects destined to fail is paramount to prevent unwanted costs and wasted effort. Although neglected diseases drug discovery is driven more by unmet medical need rather than financial considerations, the need to minimise wasted money and resources is even more vital in this under- funded area. To ensure any drug discovery project is addressing the requirements of the patients and health care providers and delivering a benefit over existing therapies, the ideal attributes of a novel drug needs to be pre-defined by a set of criteria called a target product profile. Using a target product profile the drug discovery process, clinical study design, and compound characteristics can be defined all the way back through to the suitability or druggability of the intended biochemical target. Assessment and prioritisation of the most promising targets for entry into screening programmes is crucial for maximising chances of success.

In this article, we discuss the merits of both target-based and phenotypic screening strategies to find starting points for drug discovery projects in neglected tropical disease including: human African trypanosomiasis, Chagas disease, leishmaniasis and malaria. Technological advances now mean that it is possible to undertake high quality screens against isolated molecular targets at considerable scale. However target selection is a minefield of potential issues and often molecules identified and developed as potent inhibitors of targets do not translate into actives against the whole parasite. The potential for rapid resistance development is also a key issue when tackling individual molecular targets. In phenotypic screening, compounds are screened against the whole organism, looking for activity without a priori knowledge of the target(s) being modulated. This approach brings the benefits of increased chances of efficacy and potentially slowed resistance development of a successful medicine but the lack of knowledge of the molecular target can make the optimisation process more challenging. Advances in screening technologies has now brought phenotypic approaches up to the scale attained by target-based approaches and we discuss opportunities for advances in this arena concluding that a robust drug discovery portfolio for such diseases should include both phenotypic and target-based approaches.

Pandemic, epidemic and endemic infectious diseases are united by a common problem: how do we rapidly and cost-effectively identify potential pharmacological interventions to treat infections? Given the large number of emerging and neglected infectious diseases and the fact that they disproportionately afflict the poorest members of the global society, new ways of thinking are required to develop high productivity discovery systems that can be applied to a large number of pathogens. The growing availability of parasite genome data provides the basis for developing methods to prioritize, a priori potential drug targets and analyze the pharmacological landscape of an infectious disease. Thus the overall objective of infectious disease informatics is to enable the rapid generation of plausible, novel medical hypotheses of testable pharmacological experiments, by uncovering undiscovered relationships in the wealth of biomedical literature and databases that were collected for other purposes. In particular our goal is to identify potential drug targets present in a pathogen genome and prioritize which pharmacological experiments are most likely to discover drug-like lead compounds rapidly against a pathogen (i.e. which specific compounds and drug targets should be screened, in which assays and where they can be sourced). An integral part of the challenge is the development and integration of methods to predict druggability, essentiality, synthetic lethality and polypharmocology in pathogen genomes, while simultaneously integrating the inevitable issues of chemical tractability and the potential for acquired drug resistance from the start.