The role of modern drug discovery in the fight against neglected and tropical diseases

Neglected and tropical diseases affect a large proportion of the world's population and impose a huge economic and health burden on developing countries. Despite this, there is a dearth of safe, effective, suitable medications for treatment of these diseases, largely as a result of an underinvestment in developing new drugs against these diseases by the majority of research-based pharmaceutical companies. In the past 12 years, the situation has begun to improve with the emergence of public-private product development partnerships (PDPs), which foster a collaborative approach to drug discovery and have established strong drug development pipelines for neglected and tropical diseases. Some large pharmaceutical companies have also now established dedicated research sites for developing world diseases and are working closely with PDPs on drug development activities. However, drug discovery in this field is still hampered by a lack of sufficient funding and technological investment, and there is a shortage of the tools, assays, and well-validated targets needed to ensure strong drug development pipelines in the future. The availability of high-quality chemically diverse compound libraries to enable lead discovery remains one of the critical bottlenecks. The pharmaceutical industry has much that it can share in terms of drug discovery capacity, know-how, and expertise, and in some cases has been moving towards new paradigms of collaborative pre-competitive research with the PDPs and partners. The future of drug discovery for neglected and tropical diseases will depend on the ability of those working in the area to collaborate together and will require sustained resourcing and focus.

[1]  David M. Shackleford,et al.  Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. , 2011, Journal of medicinal chemistry.

[2]  E. Winzeler,et al.  The Activities of Current Antimalarial Drugs on the Life Cycle Stages of Plasmodium: A Comparative Study with Human and Rodent Parasites , 2012, PLoS medicine.

[3]  Jeremy N. Burrows,et al.  The state of the art in anti-malarial drug discovery and development. , 2011 .

[4]  J. Baird,et al.  Targeting the hypnozoite reservoir of Plasmodium vivax: the hidden obstacle to malaria elimination. , 2010, Trends in parasitology.

[5]  J. Burrows,et al.  The global pipeline of new medicines for the control and elimination of malaria , 2012, Malaria Journal.

[6]  Pilho Kim,et al.  PA-824 Kills Nonreplicating Mycobacterium tuberculosis by Intracellular NO Release , 2008, Science.

[7]  B. Slatko,et al.  Anti-Wolbachia drug discovery and development: safe macrofilaricides for onchocerciasis and lymphatic filariasis , 2013, Parasitology.

[8]  L. Kobzik,et al.  Immunopathology and Infectious Diseases Dominant Role of the sst 1 Locus in Pathogenesis of Necrotizing Lung Granulomas during Chronic Tuberculosis Infection and Reactivation in Genetically Resistant Hosts , 2010 .

[9]  D. Leroy,et al.  Challenges in antimalarial drug discovery. , 2011, Future medicinal chemistry.

[10]  A. Diacon,et al.  14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial , 2012, The Lancet.

[11]  K. Johnston,et al.  Overcoming the Challenges of Drug Discovery for Neglected Tropical Diseases , 2014, Journal of biomolecular screening.

[12]  D. Pompliano,et al.  Drugs for bad bugs: confronting the challenges of antibacterial discovery , 2007, Nature Reviews Drug Discovery.

[13]  Jeremy N. Burrows,et al.  The Open Access Malaria Box: A Drug Discovery Catalyst for Neglected Diseases , 2013, PloS one.

[14]  J. Cano,et al.  Leishmaniasis Worldwide and Global Estimates of Its Incidence , 2012, PloS one.

[15]  David M. Shackleford,et al.  3,5-Diaryl-2-aminopyridines as a novel class of orally active antimalarials demonstrating single dose cure in mice and clinical candidate potential. , 2012, Journal of medicinal chemistry.

[16]  Jeremy N. Burrows,et al.  P. falciparum In Vitro Killing Rates Allow to Discriminate between Different Antimalarial Mode-of-Action , 2012, PloS one.

[17]  Gee Young Suh,et al.  Delamanid for multidrug-resistant pulmonary tuberculosis. , 2012, The New England journal of medicine.

[18]  N. Day,et al.  Artemisinin resistance: current status and scenarios for containment , 2010, Nature Reviews Microbiology.

[19]  J. Grosset,et al.  Promising Antituberculosis Activity of the Oxazolidinone PNU-100480 Relative to That of Linezolid in a Murine Model , 2008, Antimicrobial Agents and Chemotherapy.

[20]  J. Habbema,et al.  Can ivermectin mass treatments eliminate onchocerciasis in Africa? , 2002, Bulletin of the World Health Organization.

[21]  Bernadette A. Thomas,et al.  Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010 , 2012, The Lancet.

[22]  Richard Elliott Four lessons from global health drug discovery: medicine for an ailing industry? , 2012, ACS medicinal chemistry letters.

[23]  D. Bellows,et al.  Evaluation of the Mycobacterium smegmatis and BCG models for the discovery of Mycobacterium tuberculosis inhibitors. , 2010, Tuberculosis.

[24]  J. Butera Phenotypic screening as a strategic component of drug discovery programs targeting novel antiparasitic and antimycobacterial agents: an editorial. , 2013, Journal of medicinal chemistry.

[25]  Bruce Russell,et al.  Spiroindolones, a Potent Compound Class for the Treatment of Malaria , 2010, Science.