A novel CDPK1 inhibitor—a potential treatment for cryptosporidiosis in calves?

Abstract

Cryptosporidium parvum is a zoonotic agent that infects humans and animals occasionally causing severe, watery diarrhoea. In immunocompetent hosts, cryptosporidiosis is self-limiting but can have a fatal outcome in immunocompromised individuals. Cryptosporidium is one of the most common causes of waterborne diseases (recreational water and drinking water) in humans, a leading cause of moderate to severe childhood diarrhoea, and a major agent of diarrhoea in calves leading to high economic losses and up to 10% lethality. So far, available treatment options are insufficient for both veterinary and human clinical disease cases. Here, we report for the first time that the novel bumped kinase inhibitor (BKI) 1294 targeting the calcium-dependent protein kinase 1 (CDPK1) of Cryptosporidium is able to reduce the oocyst shedding of C. parvum by calves--its natural host--without obvious side effects.

Novel Bumped Kinase Inhibitors Are Safe and Effective Therapeutics in the Calf Clinical Model for Cryptosporidiosis

“…While treated calves had better clinical health scores, firmer stools, and a 94% reduction in oocyst shedding as compared to controls, no significant reduction in diarrhea was observed, based on fecal volumes. Lendner et al also reported a good parasitological outcome in calves treated with BKI-1294 at 10 mg/kg every other day, but calves in that preliminary report developed few clinical symptoms to evaluate conclusively [24]. Subsequent pharmacokinetic data from calves in the present report indicate that the allometrically determined dosage we (and Lendner et al [24]) used was suboptimal, with stool and plasma BKI levels that were essentially zero on the second day after each dosing.…”

“…Lendner et al also reported a good parasitological outcome in calves treated with BKI-1294 at 10 mg/kg every other day, but calves in that preliminary report developed few clinical symptoms to evaluate conclusively [24]. Subsequent pharmacokinetic data from calves in the present report indicate that the allometrically determined dosage we (and Lendner et al [24]) used was suboptimal, with stool and plasma BKI levels that were essentially zero on the second day after each dosing. Given these pharmacokinetics data and considering the accelerated gastrointestinal transit time resulting from diarrhea, we hypothesized that more-frequent dosing would result in better treatment outcomes.…”

“…Most recently, the calcium-dependent protein kinase 1 of C. parvum (CpCDPK1) has shown promising potential as a drug target in treatment of cryptosporidiosis, as well as other diseases caused by apicomplexan parasites [22][23][24][25][26]. Apicomplexan CDPK homologs have crucial roles in host cell invasion, micronemal secretion, and gliding motility [23,[27][28][29][30].…”

“…Treatment with BKI-1294 reduced C. parvum infection in vitro and eliminated infection in 6 of 7 immunodeficient mice [23]. In a preliminary report using a semiquantitative method to measure oocyst output, treatment of C. parvum-infected calves with BKI-1294 commencing 1 hour after challenge reduced oocyst shedding; however, the effect on diarrhea was inconclusive, and it was determined that further studies were needed [24].…”

In Vitro and In Vivo Effects of the Bumped Kinase Inhibitor 1294 in the Related Cyst-Forming Apicomplexans Toxoplasma gondii and Neospora caninum

“…In turn, chronic infection is characterized by the formation of intracellular tissue cysts in brain and muscular tissues that harbor slowly proliferating bradyzoites. Calcium-dependent protein kinases (CDPKs), encoded by apicoplast-associated genes and, thus, only found in apicomplexan parasites and plants, represent excellent drug targets in several apicomplexans such as Plasmodium falciparum (6), Cryptosporidium parvum (7,8) where novel drug targets are of crucial interest (9), N. caninum (10), Eimeria tenella, and Babesia bovis (11). Excellent correlations between cell activity and CDPK1 inhibition were achieved by compounds from a focused bumped kinase inhibitor (BKI) library.…”