Cryptosporidiosis Drug Discovery: Opportunities and Challenges

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.

A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis

“…A very safe drug profile is thus a key component of the target product profile18,19. KDU731 has a selectivity index of more than 100 (CC 50 HepG2 = 15.6 μM and CpCPE EC 50 = 0.1 μM) (Extended Data Table 1).…”

Recent Breakthroughs and Ongoing Limitations in Cryptosporidium Research

“…There are several constraints to drug development for cryptosporidiosis 4, 12 . The pathogenesis of the disease and the molecules and pathways that can be targeted for drug development are poorly understood 13 .…”

“…Primary human and bovine IEC models permit infections and Cryptosporidium hominis and C. parvum , respectively 16, 17 , and C. parvum infection in a non-cancer-derived IEC line, FHs 74 Int, has also been reported 18 . However, these cell lines support C. parvum infection for only a few days, do not permit completion of the life cycle or continuous propagation 12 , and can display variation in gene expression depending on culture conditions 19 . Cell-free systems for C. parvum culture have been reported 20 , but although the parasite was observed to complete its life cycle by transmission electron microscopy 21 , these in vitro axenic systems do not permit investigations of the parasite interactions with the host epithelia.…”

“…However, the small size of the model is a limitation for large-scale propagation. Additionally, the culture system employs transformed adenocarcinoma-derived Caco-2 and HT29-MTX cells, which are not representative of primary human IEC cells in vivo 12 .…”

Editorial: Drug Development for Parasite-Induced Diarrheal Diseases

“…In spite of the reported efficacy of nitroimidazole drugs, treatment failures in giardiasis occur in up to 20% of cases and a recent report from the Hospital for Tropical Diseases, London found that the nitroimidazole therapy failure rate in giardiasis was 40.2% in 2013 (Nabarro et al, 2015). Nitazoxanide, the only treatment option for cryptosporidiosis, has an efficacy ranging from 56% in malnourished children to 80% in healthy adults and it is not effective for immunocompromised patients (Manjunatha et al, 2016). All these factors make the development of new antimicrobials to treat these infections a critical need to avert future outbreaks and deaths.…”