Advancing Drug Innovation for Neglected Diseases—Criteria for Lead Progression

The current drug R&D pipeline for most neglected diseases remains weak, and unlikely to support registration of novel drug classes that meet desired target product profiles in the short term. This calls for sustained investment as well as greater emphasis in the risky upstream drug discovery. Access to technologies, resources, and strong management as well as clear compound progression criteria are factors in the successful implementation of any collaborative drug discovery effort. We discuss how some of these factors have impacted drug discovery for tropical diseases within the past four decades, and highlight new opportunities and challenges through the virtual North–South drug discovery network as well as the rationale for greater participation of institutions in developing countries in product innovation. A set of criteria designed to facilitate compound progression from screening hits to drug candidate selection is presented to guide ongoing efforts

Development of and Access to Products for Neglected Diseases

INTRODUCTION: Prior research on neglected disease drug development suggested inadequate funding was responsible for relatively few new approvals. In response, significantly more resources have been allocated towards development of drugs targeting neglected diseases. Our objective was to reassess drug development between 1975 and 1999, evaluate progress in neglected disease drug development since 2000, and explain how increased numbers of approvals are a necessary but insufficient condition to improving access. METHODS: To assess numbers of approvals targeting neglected diseases, we employed two distinct methodologies: First, to revisit numbers published in Trouiller et al. (2002) we used their method to count marketed new chemical entities (NCEs) between 1975 and 1999. Second, using the G-Finder report as a benchmark, we identified which diseases are currently considered "neglected" to tally approvals in the 1975-1999 and 2000-2009 periods. Searching PharmaProjects and IMS R&D Focus databases as well as websites from numerous drug regulatory agencies, we identified new drug approvals and indications. Also, we examined the World Health Organization's (WHO) Essential Drug List (EDL) to see which drugs and indications were on the list. FINDINGS: Upon recount, using Trouiller et al. methodology, we found that between 1975 and 1999 more NCEs (n = 32) targeting tropical diseases and tuberculosis were approved than reported in Trouiller et al. (n = 16). Using the G-Finder method of defining neglected diseases, we found 46 new drug approvals between 1975 and 1999. WHO included 85% of these drugs on the EDL. In the period 2000 to May 2009, despite much greater funding, only 26 new drugs and vaccines for neglected diseases were marketed. Of these, WHO placed 50% on the EDL. CONCLUSIONS: Product approvals for neglected diseases have increased, though progress has been uneven, with malaria appearing to benefit most in the short run from increased funding, while less success has been booked in other disease categories. Uneven progress suggests funding could be better targeted, particularly with regard to neglected diseases that have hitherto received scant attention. In addition, policymakers should focus on other aspects related to access. Besides drug development, there are the issues of EDL listing, architecture, availability, affordability, and adoption

Trypanocidal and leishmanicidal activity of six limonoids

Six limonoids [kotschyienone A and B (1, 2), 7-deacetylgedunin (3), 7-deacetyl-7-oxogedunin (4), andirobin (5) and methyl angolensate (6)] were investigated for their trypanocidal and leishmanicidal activities using bloodstream forms of Trypanosoma brucei and promastigotes of Leishmania major. Whereas all compounds showed anti-trypanosomal activity, only compounds 1–4 displayed anti-leishmanial activity. The 50% growth inhibition (GI 50) values for the trypanocidal and leishmanicidal activity of the compounds ranged between 2.5 and 14.9 μM. Kotschyienone A (1) was found to be the most active compound with a minimal inhibition concentration (MIC) value of 10 μM and GI 50 values between 2.5 and 2.9 μM. Only compounds 1 and 3 showed moderate cytotoxicity against HL-60 cells with MIC and GI 50 values of 100 μM and 31.5–46.2 μM, respectively. Compound 1 was also found to show activity against intracellular amastigotes of L. major with a GI 50 value of 1.5 μM. The results suggest that limonoids have potential as drug candidates for the development of new treatments against trypanosomiasis and leishmaniasis

TDR Targets: a chemogenomics resource for neglected diseases

The TDR Targets Database (http://tdrtargets.org) has been designed and developed as an online resource to facilitate the rapid identification and prioritization of molecular targets for drug development, focusing on pathogens responsible for neglected human diseases. The database integrates pathogen specific genomic information with functional data (e.g. expression, phylogeny, essentiality) for genes collected from various sources, including literature curation. This information can be browsed and queried using an extensive web interface with functionalities for combining, saving, exporting and sharing the query results. Target genes can be ranked and prioritized using numerical weights assigned to the criteria used for querying. In this report we describe recent updates to the TDR Targets database, including the addition of new genomes (specifically helminths), and integration of chemical structure, property and bioactivity information for biological ligands, drugs and inhibitors and cheminformatic tools for querying and visualizing these chemical data. These changes greatly facilitate exploration of linkages (both known and predicted) between genes and small molecules, yielding insight into whether particular proteins may be druggable, effectively allowing the navigation of chemical space in a genomics context

Activity of the antiarrhythmic drug amiodarone against Leishmania (L.) infantum: an in vitro and in vivo approach

<div><p>Abstract Background: Considering the high toxicity and limited therapies available for treating visceral leishmaniasis (VL), the drug repositioning approach represents a faster way to deliver new therapies to the market. Methods: In this study, we described for the first time the activity of a potent antiarrhythmic, amiodarone (AMD), against L. (L.)infantum and its in vitro and in vivo activity. Results: The evaluation against promastigotes has shown that amiodarone presents leishmanicidal effect against the extracellular form, with an IC50 value of 10 μM. The activity was even greater against amastigotes in comparison with promastigotes with an IC50 value of 0.5 μM. The selectivity index in relation to the intracellular form demonstrated that the antiparasitic activity was approximately 56 times higher than its toxicity to mammalian cells. Investigation of the in vivo AMD activity in the L. infantum-infected hamster model showed that 51 days after the initial infection, amiodarone was unable to reduce the parasite burden in the spleen and liver when treated for 10 consecutive days, intraperitoneally, at 50 mg/kg/day, as determined by qPCR. Although not statistically significant, AMD was able to reduce the parasite burden by 20% in the liver when treated for 10 consecutive days, orally, at 100 mg/kg/day; no reduction in the spleen was found by qPCR. Conclusions: Our findings may help further drug design studies seeking new AMD derivatives that may provide new candidates with an in vitro selectivity close to or even greater than that observed in the prototype delivering effectiveness in the experimental model of VL.</p></div

A Kernel for Open Source Drug Discovery in Tropical Diseases

Open source drug discovery, a promising alternative avenue to conventional patent-based drug development, has so far remained elusive with few exceptions. A major stumbling block has been the absence of a critical mass of preexisting work that volunteers can improve through a series of granular contributions. This paper introduces the results from a newly assembled computational pipeline for identifying protein targets for drug discovery in ten organisms that cause tropical diseases. We have also experimentally tested two promising targets for their binding to commercially available drugs, validating one and invalidating the other. The resulting kernel provides a base of drug targets and lead candidates around which an open source community can nucleate. We invite readers to donate their judgment and in silico and in vitro experiments to develop these targets to the point where drug optimization can begin

A “reverse pharmacology” approach for developing an anti-malarial phytomedicine

A “reverse pharmacology” approach to developing an anti-malarial phytomedicine was designed and implemented in Mali, resulting in a new standardized herbal anti-malarial after six years of research. The first step was to select a remedy for development, through a retrospective treatment-outcome study. The second step was a dose-escalating clinical trial that showed a dose-response phenomenon and helped select the safest and most efficacious dose. The third step was a randomized controlled trial to compare the phytomedicine to the standard first-line treatment. The last step was to identify active compounds which can be used as markers for standardization and quality control. This example of “reverse pharmacology” shows that a standardized phytomedicine can be developed faster and more cheaply than conventional drugs. Even if both approaches are not fully comparable, their efficiency in terms of public health and their complementarity should be thoroughly considered

Assay strategies for the discovery and validation of therapeutics targeting <i>Brugia pahangi</i> Hsp90

The chemotherapy of lymphatic filariasis relies upon drugs such as diethylcarbamazine and ivermectin that largely target the microfilarial stages of the parasite, necessitating continued treatment over the long reproductive life span of the adult worm. The identification of compounds that target adult worms has been a long-term goal of WHO. Here we describe a fluorescence polarization assay for the identification of compounds that target Hsp90 in adult filarial worms. The assay was originally developed to identify inhibitors of Hsp90 in tumor cells, and relies upon the ability of small molecules to inhibit the binding of fluorescently labelled geldanamycin to Hsp90. We demonstrate that the assay works well with soluble extracts of Brugia, while extracts of the free-living nematode C. elegans fail to bind the probe, in agreement with data from other experiments. The assay was validated using known inhibitors of Hsp90 that compete with geldanamycin for binding to Hsp90, including members of the synthetic purine-scaffold series of compounds. The efficacy of some of these compounds against adult worms was confirmed in vitro. Moreover, the assay is sufficiently sensitive to differentiate between binding of purine-scaffold compounds to human and Brugia Hsp90. The assay is suitable for high-throughput screening and provides the first example of a format with the potential to identify novel inhibitors of Hsp90 in filarial worms and in other parasitic species where Hsp90 may be a target