br Chagas disease Chagas disease
Chagas disease Chagas disease, an NTD caused by the protozoan Trypanosoma cruzi, affects 8–10 million people globally. More than 10,000 deaths are caused by the disease each year, and nearly 70 million people are susceptible to infection (Manne-Goehler, Umeh, Montgomery, & Wirtz, 2016). Chagas disease is endemic across 21 Latin American countries, where it is the leading cause of Q-VD(OMe)-OPh failure. Outside of the endemic regions, the USA is the most affected country, with nearly 240,000 cases of the disease (Manne-Goehler et al., 2016, Montgomery et al., 2014). Chagas disease is characterized by acute and chronic clinical phases. The acute phase, which lasts for approximately 8weeks, can be asymptomatic or cause mild symptoms. The majority of infected individuals (60% to 70%) pass through the acute phase without evolving to chronic disease. However, the remaining 30% to 40% develops chronic Chagas disease, which is an incurable condition (Bern, 2015). Pharmacological treatment is limited to benznidazole (1) (Rochagan®, Roche), a nitroimidazole identified in 1971, and nifurtimox (2) (Lampit®, Bayer), a nitrofuran discovered in 1965 (Fig. 1). These drugs are useful in the acute phase only and are completely ineffective in chronic Chagas disease. Moreover, adverse effects, such as allergic skin reactions, gastrointestinal symptoms, nerve toxicity and fever, frequently result in poor treatment adhesion (Muñoz, Murcia, & Segovia, 2011). Compared with nifurtimox, benznidazole is less toxic and is therefore adopted as the first-line treatment (Castro et al., 2006, Viotti et al., 2009). The shortcomings of these drugs prevent millions of people from obtaining adequate treatment, demonstrating the need for novel therapeutic agents for Chagas disease.
Human African trypanosomiasis HAT, also known as sleeping sickness, is an NTD that affects poor populations on the African continent. Caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, 10,000 new cases of the disease are registered each year, and 70 million people are vulnerable to infection (Franco, Simarro, Diarra, & Jannin, 2014). T. b. gambiense-HAT occurs in 24 countries, particularly in central and western Africa, which account for 90% of the cases. T. b. rhodesiense-HAT prevails in 13 countries, mainly in east Africa, and accounts for 10% of the total burden. The disease has two clinical phases, early- and late-stage HAT. The early stage (also called the hemolymphatic phase) persists for months, provoking fever, headaches, prostration, pain in the joints, and lymphadenopathy. Untreated patients evolve to late-stage HAT, termed the neurological phase, in which the parasite crosses the blood-brain barrier (BBB) and reaches the central nervous system (CNS). The resulting neurological deterioration leads to sleep alterations, psychiatric disorders and sensorial disturbances, which ultimately culminate in coma and death (MacLean, Reiber, Kennedy, & Sternberg, 2012). Chemotherapy consists of drugs characterized by poor efficacy and outstanding toxicity (Kennedy, 2013). Suramin (3) and pentamidine (4), two compounds discovered in the 1920s, are unable to penetrate the BBB and are therefore used in early-stage HAT only (Fig. 2). In addition, pentamidine can lead to fatal hypoglycemia. Melarsoprol (5), a remarkably toxic chemical identified in 1949, is effective against both sub-species. However, as it causes lethal reactive encephalopathy in up to 10% of patients, it is restricted to the late-stage disease only. Eflornithine (6), the most recent drug and the first-line treatment for T. b. gambiense late-stage HAT, was licensed in 1990 (Simarro, Franco, Diarra, Postigo, & Jannin, 2012). Nifurtimox (2) has been used since 2009, along with eflornithine. Nifurtimox-eflornithine combination therapy (NECT) has been demonstrated to be effective in reducing the duration of treatment in T. b. gambiense late-stage HAT (Alirol et al., 2013). Despite the existence of these alternatives, the lack of a safe and effective agent that is active against both sub-species in the early and late stages of the disease represents a critical need for new drugs for HAT (Simarro et al., 2012).