Perspective pubs.acs.org/journal/aidcbc
Cryptosporidiosis Drug Discovery: Opportunities and Challenges Ujjini H. Manjunatha,* Alexander T. Chao, F. Joel Leong, and Thierry T. Diagana* Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01, Singapore 138670 ABSTRACT: The apicomplexan parasite Cryptosporidium is the second most important diarrheal pathogen causing life-threatening diarrhea in children, which is also associated with long-term growth faltering and cognitive deficiency. Cryptosporidiosis is a parasitic disease of public health concern caused by Cryptosporidium parvum and Cryptosporidium hominis. Currently, nitazoxanide is the only approved treatment for cryptosporidium infections. Unfortunately, it has limited efficacy in the most vulnerable patients, thus there is an urgent need for a safe and efficacious cryptosporidiosis drug. In this work, we present our current perspectives on the target product profile for novel cryptosporidiosis therapies and the perceived challenges and possible mitigation plans at different stages in the cryptosporidiosis drug discovery process. KEYWORDS: Cryptosporidium, cryptosporidiosis, drug discovery, target product profile, diarrhea
■
CRYPTOSPORIDIOSIS, GLOBAL BURDEN For children under the age of 5 years, infectious diarrhea is the second leading cause of death, accounting for 800 000 deaths annually.1 Despite the reduction in mortality over the last 20 years primarily due to improvements in the provision of safe water and sanitation, these statistics are sobering. In developing countries, children under 3 years old experience on average three diarrheal episodes every year, with stunted growth a common sequelae.2 Indeed, diarrhea is a major cause of malnutrition, and malnourished children are more likely to fall ill from diarrhea. Diarrhea is caused by a wide-range of pathogens, including viruses (e.g., Rotavirus and Norovirus), bacteria (e.g., enterotoxigenic E. coli, Campylobacter spp., Shigella spp., and Vibrio cholera), and protozoan parasites (e.g., Cryptosporidium spp., Giardia intestinalis, and Entamoeba histolytica). Though the continuous improvement of sanitation, the water supply, and the deployment of rotavirus vaccinations will surely contribute to the further reduction of the infectious diarrheal diseases burden, better chemotherapeutic options against diarrheal pathogens are required. The Global Enteric Multicenter Study (GEMS) examined the epidemiology and etiology of pediatric moderate-to-severe diarrhea in sub-Saharan Africa and parts of Asia.3 A major and unexpected result of this study was the finding that in children under 2 years of age Cryptosporidium is the second leading pathogen causing life-threatening diarrhea and is also associated with growth stunting.3,4 In another recent study of malnutrition and enteric diseases (MAL-ED), Cryptosporidium spp. infection had the highest attributable burden of diarrhea in 1 year old children.5 Cryptosporidiosis is particularly associated with prolonged (7−14 days) and persistent (>14 days) diarrhea.6,7 Cryptosporidiosis is also more frequent and contributes to a higher mortality rate in malnourished children.8,9 Moreover, malnutrition predisposes patients to infection, thus creating a © XXXX American Chemical Society
vicious cycle of malnutrition−Cryptosporidium infection associated with long-term growth stunting and cognitive deficits.10 In sub-Saharan Africa and some South Asian countries alone, Cryptosporidium is estimated to contribute to more than 200 000 deaths in children aged
