DNDi Publications

In vitro and in vivo experimental models for drug screening and development for chagas disease by Romanha et al. 2010

Chagas disease, a neglected illness, affects nearly 12-14 million people in endemic areas of Latin America. Although the occurrence of acute cases sharply has declined due to Southern Cone Initiative efforts to control vector transmission, there still remain serious challenges, including the maintenance of sustainable public policies for Chagas disease control and the urgent need for better drugs to treat chagasic patients. Since the introduction of benznidazole and nifurtimox approximately 40 years ago, many natural and synthetic compounds have been assayed against Trypanosoma cruzi, yet only a few compounds have advanced to clinical trials. This reflects, at least in part, the lack of consensus regarding appropriate in vitro and in vivo screening protocols as well as the lack of biomarkers for treating parasitaemia. The development of more effective drugs requires (i) the identification and validation of parasite targets, (ii) compounds to be screened against the targets or the whole parasite and (iii) a panel of minimum standardised procedures to advance leading compounds to clinical trials. This third aim was the topic of the workshop entitled Experimental Models in Drug Screening and Development for Chagas Disease, held in Rio de Janeiro, Brazil, on the 25th and 26th of November 2008 by the Fiocruz Program for Research and Technological Development on Chagas Disease and Drugs for Neglected Diseases Initiative. During the meeting, the minimum steps, requirements and decision gates for the determination of the efficacy of novel drugs for T. cruzi control were evaluated by interdisciplinary experts and an in vitro and in vivo flowchart was designed to serve as a general and standardised protocol for screening potential drugs for the treatment of Chagas disease.

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2009

Chagas in the United States: Increasing Prevalence, Continued Neglect by Drugs for Neglected Diseases Initiative (DNDi), 2009
Chagas disease has traditionally been characterized as a Latin American phenomenon, endemic only to the 21 countries south of the United States border. However, recent studies have shown that the prevalence of Chagas disease outside of Latin America is increasing in large part due to population flows, and Chagas disease is becoming an important global health issue.

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New, Improved Treatments for Chagas Disease: From the R&D Pipeline to the Patients by Ribeiro I, Sevcsik AM, Alves F, Diap G, Don R, Harhay MO, Chang S, Pecoul B. In PLoS Negl Trop Dis 3(7): e484.
This policy paper outlines the urgent need for new treatments for Chagas, examines barriers to development and evaluation of new drugs, and reports on progress in bringing new treatments to patients. Part of a Chagas disease series published by PLoS NTD, this paper focuses on the efforts of DNDi and others to develop and make available better-adapted diagnostic and treatment tools. Published upon the occasion of the 100th anniversary of Chagas disease, this article also mentions a newly launched campaign, www.treatchagas.org, to increase awareness about Chagas disease, and is joined in the series by an editorial covering the unfinished public health agenda and a research article on MSF’s 10-year experience of treating Chagas disease in Latin America.

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Related articles in the series:

• Franco-Paredes C, Bottazzi ME, Hotez PJ (2009). The Unfinished Public Health Agenda of Chagas Disease in the Era of Globalization. PLoS Negl Trop Dis 3(7): e470. Click here to access full-text article.
• Yun O, Lima MA, Ellman T, Chambi W, Castillo S, et al. (2009). Feasibility, Drug Safety, and Effectiveness of Etiological Treatment Programs for Chagas Disease in Honduras, Guatemala and Bolivia: 10-Year Experience of Médecins Sans Frontières. PLoS Negl Trop Dis 3(7): e488. Click here to access full-text article.

Drug discovery for neglected diseases: View of a public-private partnership by Chatelain E, Don R. In Antiparasitic Antibacterial Drug Discovery by Paul M. Selzer (Ed); 2009 Apr: Wiley-Blackwell.
In answer to the lack of modern and effective drugs for diseases such as human African trypanosomiasis (HAT; sleeping sickness) and Chagas disease which present no financial viability for the pharmaceutical industry, new models of drug discovery have been developed.
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Natural Products for Neglected Diseases: A Review by Ioset JR. Current Organic Chemistry 2008 May; 12 (8): 643-666.
Neglected diseases are responsible for high mortality and morbidity each year in low-income countries. Due to the lack of vaccines and of safe, effective and affordable treatments, there is an urgent need to reinforce the existing therapeutic arsenal against these killers. One of the main opportunities is through the discovery of new molecules from natural origin. The gaps identified in the R&D process aiming to deliver new medicines for neglected diseases however also apply to natural products. A key review of the most promising antiprotozoal molecules recently discovered from natural resources is presented here together with a critical update on their current development status.
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The Challenges of Chagas Disease - Grim Outlook or Glimmer of Hope? By Tarleton RL, Reithinger R, Urbina JA, Kitron U, Gürtler RE. Plos Med 2007 Dec; 4 (12): 1852-1857.
Despite estimates of up to 15 million existing cases and 50,000–200,000 new infections per year, funding for research, prevention, and control has been limited, and therapeutic options remain unsatisfactory. Consequently, several editorials and perspectives have recently drawn attention to Chagas disease and T. cruzi [8–10]. While these papers highlighted the impact of this disease on public health in the Americas, and rightly pointed out that major achievements have been made in its control, they failed to emphasize several key challenges that are currently undermining these achievements and that must be urgently addressed in order to move to the next stage: ensuring the long-term and sustainable control of this devastating disease.
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Inhibition of Trypanosoma cruzi Hexokinase by Bisphosphonates by Hudock MP, Sanz-Rodriguez CE, Song Y, Chan JM, Zhang Y, Odeh S, Kosztowski T, Leon-Rossell A, Concepcion JL, Yardley V, Croft SL, Urbina JA, Oldfield E. J Med Chem. 2006 Jan 12;49(1):215-23.
Hexokinase is the first enzyme involved in glycolysis in most organisms, including the etiological agents of Chagas disease (Trypanosoma cruzi) and African sleeping sickness (Trypanosoma brucei). The T. cruzi enzyme is unusual since, unlike the human enzyme, it is inhibited by inorganic diphosphate (PPi).
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Preparation of transition-state analogues of sterol 24-methyl transferase as potential anti-parasitics by Lorente SO, Jimenez CJ, Gros L, Yardley V, de Luca-Fradley K, Croft SL, A Urbina J, Ruiz-Perez LM, Pacanowska DG, Gilbert IH. Bioorg. Med. Chem. 2005 Jul, 13: 5435-5453.
In this paper we discuss the design, synthesis and evaluation of potential transition state analogues of the enzyme D24(25)-methyltransferase (24-SMT). This enzyme is essential for the biosynthesis of ergosterol, but not required for the biosynthesis of cholesterol. A series of compounds were successfully synthesised in which mimics of the S-adenosyl methionine co-factor were attached to the sterol nucleus.
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