Analysis of pan-African Centres of excellence in health innovation highlights opportunities and challenges for local innovation and financing in the continent.

A pool of 38 pan-African Centres of Excellence (CoEs) in health innovation has been selected and recognized by the African Network for Drugs and Diagnostics Innovation (ANDI), through a competitive criteria based process. The process identified a number of opportunities and challenges for health R&D and innovation in the continent: i) it provides a direct evidence for the existence of innovation capability that can be leveraged to fill specific gaps in the continent; ii) it revealed a research and financing pattern that is largely fragmented and uncoordinated, and iii) it highlights the most frequent funders of health research in the continent. The CoEs are envisioned as an innovative network of public and private institutions with a critical mass of expertise and resources to support projects and a variety of activities for capacity building and scientific exchange, including hosting fellows, trainees, scientists on sabbaticals and exchange with other African and non-African institutions.

Traditional medicines as a mechanism for driving research innovation in Africa.

The outcomes from recent high profile deliberations concerning African health research and economic development all point towards the need for a mechanism to support health innovation on the continent. The mission of the African Network for Drugs and Diagnostics Innovation (ANDI), is to promote and sustain African-led health product innovation to address African public health needs through the assembly of research networks, and building of capacity to support human and economic development. ANDI is widely viewed as the vehicle to implementing some of these recommendations. There is tremendous opportunity for Africa, to leverage the expertise in natural products and traditional medicines in support of this objective to kick-start innovation. This report highlights key recommendations that have emerged through expert forums convened by ANDI on the challenges, opportunities and prospects for investing in this important area of research.

CRIMALDDI: a co-ordinated, rational, and integrated effort to set logical priorities in anti-malarial drug discovery initiatives.

Despite increasing efforts and support for anti-malarial drug R&D, globally anti-malarial drug discovery and development remains largely uncoordinated and fragmented. The current window of opportunity for large scale funding of R&D into malaria is likely to narrow in the coming decade due to a contraction in available resources caused by the current economic difficulties and new priorities (e.g. climate change). It is, therefore, essential that stakeholders are given well-articulated action plans and priorities to guide judgments on where resources can be best targeted.The CRIMALDDI Consortium (a European Union funded initiative) has been set up to develop, through a process of stakeholder and expert consultations, such priorities and recommendations to address them. It is hoped that the recommendations will help to guide the priorities of the European anti-malarial research as well as the wider global discovery agenda in the coming decade.

Synthesis and structure-activity relationships of antimalarial 4-oxo-3-carboxyl quinolones.

Malaria is endemic in tropical and subtropical regions of Africa, Asia, and the Americas. The increasing prevalence of multi-drug-resistant Plasmodium falciparum drives the ongoing need for the development of new antimalarial drugs. In this light, novel scaffolds to which the parasite has not been exposed are of particular interest. Recently, workers at the Swiss Tropical Institute discovered two novel 4-oxo-3-carboxyl quinolones active against the intra-erythrocytic stages of P. falciparum while carrying out rationally directed low-throughput screening of potential antimalarial agents as part of an effort directed by the World Health Organization. Here we report the design, synthesis, and preliminary pharmacologic characterization of a series of analogues of 4-oxo-3-carboxyl quinolones. These studies indicate that the series has good potential for preclinical development.

Innovative lead discovery strategies for tropical diseases.

Lead discovery is currently a key bottleneck in the pipeline for much-needed novel drugs for tropical diseases such as malaria, tuberculosis, African sleeping sickness, leishmaniasis and Chagas disease. Here, we discuss the different approaches to lead discovery for tropical diseases and emphasize a coordination strategy that involves highly integrated partnerships and networks between scientists in academic institutions and industry in both wealthy industrialized countries and disease-endemic countries. This strategy offers the promise of reducing the inherently high attrition rate of the early stages of discovery research, thereby increasing the chances of success and enhancing cost-effectiveness.

Piloting a smartphone-based application for tracking and supply chain management of medicines in Africa.

A confounding factor for healthcare programmes in African countries is the inability of essential health tools to reach targeted locations and populations, due to poor Logistics Management Information System (LMIS). In a bid to contribute towards addressing these challenges, a pilot study was undertaken to evaluate the tracking ability, reliability and applicability of EASE App, a novel Smart Phone based Application. The App is designed to provide real-time tracking and tracing of commodities as well as curation of data in a cloud based database with restricted access which can be linked with other databases. In this study, NIPRIMAL was labelled with QR codes, and tracked within the Federal Capital Territory, Abuja, Nigeria, using the smartphone based EASE App. Data collected showed that the "EASE App" tracking had accuracy of 100% for date and time of scan, operators' codes and product identity; and 92.83±1.69% and 99.83±0.27% accuracy for GPS mapping label for the city and country, respectively. The GPS mapping label for specific streets, roads or districts, gave an accuracy of about 64.28±3.14%. The technology was able to provide real-time data on user unique identity, user location as well as date/time of use, and the feedback report indicated that it was readily deployable and easy to use. The results demonstrate that the "EASE App" is a promising technology that can support supply chain and related data management challenges in resource poor settings. The potential benefit of the EASE App in strengthening LMIS and distribution chain system in Africa as well as future optimization of the App are discussed.

Study roadmap for high-throughput development of easy to use and affordable biomarkers as diagnostics for tropical diseases: a focus on malaria and schistosomiasis.

BACKGROUND: Interventions are currently being used against 'infectious diseases of poverty', which remain highly debilitating and deadly in most endemic countries, especially malaria, schistosomiasis, echinococcosis and African sleeping sickness. However, major limitations of current 'traditional' methods for diagnosis are neither simple nor convenient for population surveillance, and showed low sensitivity and specificity. Access to novel technologies for the development of adequate and reliable tools are expressly needed. A collaborative project between African Network for Drugs and Diagnostics Innovation and partner institutions in Africa and China aims to screen suitable serological biomarkers for diagnostic pipelines against these 'diseases of the poor'. METHODS: Parasite-specific exposed versus unexposed individuals were screened and sera or urine/stools were collected through case-control studies in China and African countries. Target genes/open reading frames were selected, then will be cloned and cell-free expressed, quantified and immuno-detected. Target antigens/epitopes will be probed and screened with sera from exposed or unexposed individuals using a high-throughput antigen screening platform as the study progresses. The specificity and sensitivity of highly immunoreactive biomarkers will be evaluated as well, using enzyme-linked immunosorbent assays or dipsticks. DISCUSSION: This roadmap explicitly unfolds the integrated operating procedures with focus on malaria and schistosomiasis, for the identification of suitable biomarkers that will aid the prioritization of diagnostics for population use. However, there is need to further validate any new diagnostic through comparison with standard methods in field deployable tests for each region. Our expectations for the future are to seek regulatory approval and promote the use of diagnostics in endemic areas.

Drug discovery and beyond: the role of public-private partnerships in improving access to new malaria medicines.

Traditional pharmaceutical research and development (R&D) strategy has failed to address the desperate need for new antimalarial drugs. The populations affected are too poor to attract commercially-driven R&D. Over the last few years, a new model, the public-private partnership for product development, has radically changed the antimalarial R&D landscape. The partnerships bring together academic and industry expertise with funding from governmental, philanthropic and charitable sources. The Medicines for Malaria Venture, a not-for-profit foundation based in Geneva, aims to develop new antimalarials for developing countries through public-private partnership. It is currently managing a portfolio of around 20 projects at various stages of development. However, as in all drug R&D, some of these projects will fail. The portfolio approach helps to maximize the chances of success, but there are obvious challenges, including financial and managerial ones. Proactive management of the two vital interfaces in the drug supply chain is important for success. Upstream, basic research must be aligned with translational research in order to ensure a continuous supply of leads into the development pipeline. Meanwhile, downstream, drug discovery and development must be aligned with access to ensure optimal health impact. All stages require partnership, sustainable financing and the engagement of disease-endemic countries. The recent G8 report on Africa has lent support to mechanisms aimed at improving health and achieving the Millenium Development Goals.

Medicines for Malaria Venture new developments in antimalarials.

Choosing appropriate chemoprophylaxis and stand-by treatment for travelers will remain a problem for the near future because of resistant Plasmodium falciparum. For those who live in the malaria endemic regions of the world it is a matter of life and death, but the future looks bright for control of malaria because of the development of organizations like MMV and their ability to forge suitable partnerships to tackle really big problems. This would not be possible if it were not for the MMV Stakeholders who provide the funding necessary for the discovery and development of new drugs. Malaria is a difficult problem but even if only a few of the potential drugs in the MMV pipeline become drugs, the control of malaria may again become possible.

Identification and optimization of an aminoalcohol-carbazole series with antimalarial properties.

Recent observations on the emergence of artemisinin resistant parasites have highlighted the need for new antimalarial treatments. An HTS campaign led to the identification of the 1-(1-aminopropan-2-ol)carbazole analogues as potent hits against Plasmodium falciparum K1 strain. The SAR study and optimization of early ADME and physicochemical properties direct us to the selection of a late lead compound that shows good efficacy when orally administrated in the in vivo P. berghei mouse model.

Interview with Solomon Nwaka.

Solomon Nwaka was born in Nigeria and grew up seeing at first hand the impact of neglected diseases. His research efforts have taken him across the globe, in both the developed and developing world. Following posts in academia, industry and at the Medicines for Malaria Venture, he is now at the WHO where he is engaged in initiating schemes to support research into neglected diseases in developing countries, notably the African Network for Drugs and Diagnostics Innovation, which is now an organization under the United Nations Economic Commission for Africa. He speaks to Future Medicinal Chemistry about what inspired him to take up a career in neglected disease research and how the developing world should lead the effort to tackle some of the diseases that most affect them.

Drugs and diagnostic innovations to improve global health.

Infectious diseases remain the major cause of morbidity and mortality in the developing world. Affordable effective drugs and diagnostics are critical for patient management and disease control but the development of new drugs and diagnostics is too slow to keep up with the emergence and spread of infectious diseases around the world. Innovative collaborative research and development involving disease endemic countries and developed countries are urgently needed to accelerate progress along the path from discovery to product adoption. These emerging approaches and the need for increased investment in human and financial resources to support them are discussed.

Integrated dataset of screening hits against multiple neglected disease pathogens.

New chemical entities are desperately needed that overcome the limitations of existing drugs for neglected diseases. Screening a diverse library of 10,000 drug-like compounds against 7 neglected disease pathogens resulted in an integrated dataset of 744 hits. We discuss the prioritization of these hits for each pathogen and the strong correlation observed between compounds active against more than two pathogens and mammalian cell toxicity. Our work suggests that the efficiency of early drug discovery for neglected diseases can be enhanced through a collaborative, multi-pathogen approach.

Identification of attractive drug targets in neglected-disease pathogens using an in silico approach.

BACKGROUND: The increased sequencing of pathogen genomes and the subsequent availability of genome-scale functional datasets are expected to guide the experimental work necessary for target-based drug discovery. However, a major bottleneck in this has been the difficulty of capturing and integrating relevant information in an easily accessible format for identifying and prioritizing potential targets. The open-access resource TDRtargets.org facilitates drug target prioritization for major tropical disease pathogens such as the mycobacteria Mycobacterium leprae and Mycobacterium tuberculosis; the kinetoplastid protozoans Leishmania major, Trypanosoma brucei, and Trypanosoma cruzi; the apicomplexan protozoans Plasmodium falciparum, Plasmodium vivax, and Toxoplasma gondii; and the helminths Brugia malayi and Schistosoma mansoni. METHODOLOGY/PRINCIPAL FINDINGS: Here we present strategies to prioritize pathogen proteins based on whether their properties meet criteria considered desirable in a drug target. These criteria are based upon both sequence-derived information (e.g., molecular mass) and functional data on expression, essentiality, phenotypes, metabolic pathways, assayability, and druggability. This approach also highlights the fact that data for many relevant criteria are lacking in less-studied pathogens (e.g., helminths), and we demonstrate how this can be partially overcome by mapping data from homologous genes in well-studied organisms. We also show how individual users can easily upload external datasets and integrate them with existing data in TDRtargets.org to generate highly customized ranked lists of potential targets. CONCLUSIONS/SIGNIFICANCE: Using the datasets and the tools available in TDRtargets.org, we have generated illustrative lists of potential drug targets in seven tropical disease pathogens. While these lists are broadly consistent with the research community's current interest in certain specific proteins, and suggest novel target candidates that may merit further study, the lists can easily be modified in a user-specific manner, either by adjusting the weights for chosen criteria or by changing the criteria that are included.