Advances in bumped kinase inhibitors for human and animal therapy for cryptosporidiosis

Hulverson, Matthew A.; Choi, Ryan; Arnold, Samuel; Schaefer, Deborah A.; Hemphill, Andrew; McCloskey, Molly C.; Betzer, Dana P.; Müller, Joachim; Vidadala, Rama Subba Rao; Whitman, Grant R.; Rivas, Kasey; Barrett, Lynn K.; Hackman, Robert C.; Love, Melissa S.; McNamara, Case W.; Shaughnessy, Thomas K.; Kondratiuk, Alison; Kurnick, Matthew D; Banfor, Patricia N.; Lynch, James J.; Freiberg, Gail; Kempf, Dale J.; Maly, Dustin J.; Riggs, Michael W.; Ojo, Kayode K.; Voorhis, Wesley C. Van

doi:10.1016/j.ijpara.2017.08.006

Cited by 30 publications

(69 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently BKI-1294 treatment was applied in pregnant sheep experimentally infected with T. gondii oocysts where it was partially efficacious against T. gondii infection, and no adverse effects of drug treatment were noted in this small ruminant model [36]. BKI-1369 and BKI-1770 are lead compounds for the treatment of diarrhea caused by cryptosporidiosis in calves [15,17]. In addition, excellent BKI-1369 efficacy was demonstrated against Cystisospora suis infection in piglets [18], and in a pig model of acute diarrhea caused by Cryptosporidium hominis ([16].…”

Section: Discussionmentioning

confidence: 99%

Comparative assessment of the effects of bumped kinase inhibitors on early zebrafish embryo development and pregnancy in mice

Anghel

Winzer

Imhof

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Bumped kinase inhibitors (BKIs) are effective against a variety of apicomplexan parasites. Fifteen BKIs with promising in vitro efficacy against Neospora caninum tachyzoites, low cytotoxicity in mammalian cells, and no toxic effects in non-pregnant BALB/c mice, were assessed in pregnant mice. Drugs were emulsified in corn oil and applied by gavage for 5 days. Five BKIs did not affect pregnancy, 5 BKIs exhibited 15-35% of neonatal mortality, and 5 compounds caused strong effects (infertility, abortion, stillbirth and pup mortality). Additionally, the impact of these compounds on zebrafish (Danio rerio) embryo development was assessed by exposing freshly fertilized eggs to 0.2-50μM of BKIs and microscopical monitoring of embryo development in a blinded manner during 4 days. We propose an algorithm that includes quantification of malformations and embryo deaths, and established a scoring system that allows to calculate an impact score (Si) that indicates at which concentrations BKIs visibly affect zebrafish embryo development. Comparison of the two models showed that for 9 compounds no clear correlation between Si and pregnancy outcome was visible. However, those 3 BKIs affecting zebrafish embryos only at high concentrations (40μM or higher) did not impair mouse pregnancy at all, and those 3 compounds that inhibited zebrafish embryo development already at 0.2μM showed detrimental effects in the pregnancy model. Thus, the zebrafish embryo development test has a limited predictive value to foresee pregnancy outcome in BKI-treated mice. We conclude, that maternal health-related factors such as cardiovascular, pharmacokinetic and/or bioavailability properties also contribute to BKI-pregnancy effects.

show abstract

Section: Discussionmentioning

confidence: 99%

Comparative assessment of the effects of bumped kinase inhibitors on early zebrafish embryo development and pregnancy in mice

Anghel

Winzer

Imhof

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the present study, we used the GB piglet model to evaluate the efficacy of BKI 1369, a candidate with less potential cardiotoxicity than that of BKI 1294, using the well-characterized C. hominis strain TU502 (12). BKI 1369 has been well characterized for potency, stability, metabolism, toxicity, and pharmacokinetics and has been shown to be potent against C. parvum in infected mice and calves (13). Piglets treated with BKI 1369 exhibited a significant reduction of oocyst excretion in feces, with considerable symptomatic improvement.…”

mentioning

confidence: 99%

Therapeutic Efficacy of Bumped Kinase Inhibitor 1369 in a Pig Model of Acute Diarrhea Caused by Cryptosporidium hominis

Lee

Ginese

Beamer

et al. 2018

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Recent reports highlighting the global significance of cryptosporidiosis among children have renewed efforts to develop control measures. We evaluated the efficacy of bumped kinase inhibitor (BKI) 1369 in the gnotobiotic piglet model of acute diarrhea caused by , the species responsible for most human cases. Five-day treatment with BKI 1369 reduced signs of disease early during treatment compared to those of untreated animals. Piglets treated with BKI 1369 exhibited significant reductions of oocyst excretion, mucosal colonization by, and mucosal lesions, which resulted in considerable symptomatic improvement. BKI 1369 reduced the parasite burden and disease severity in the gnotobiotic pig model. Together these data suggest that a BKI-mediated therapeutic may be an effective treatment against cryptosporidiosis.

show abstract

“…In a calf model similar to the preceding, paromomycin demonstrated prophylactic efficacy against C. parvum challenge and proof of concept, but the drug dosage required was determined to be cost prohibitive for veterinary use [16]. While there is no universally applicable design for the calf model given geographic, institutional, and laboratory constraints, we have used the acute model described here to consistently replicate data demonstrating therapeutic efficacy for multiple bumped kinase inhibitor (BKI) drugs for further study, as well as to consistently replicate data demonstrating lower, clinically less satisfactory efficacy for other BKIs to eliminate from further study [11,17] (M.W. Riggs and D.A.…”

Section: Introductionmentioning

confidence: 99%

“…Reduction of oocyst shedding is an important treatment outcome when considering the epidemiologic importance of the environmental parasite burden and exposure risk to both humans and livestock [19]. By 8 or 9 days post infection (DPI), most untreated control calves are beginning to resolve diarrhea in this model [11,17]. Therefore, we end the experiment at 10 DPI to conclude initial efficacy determinations.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Calf Clinical Model of Cryptosporidiosis for Efficacy Evaluation of Therapeutics

Riggs

Schaefer

2019

Methods in Molecular Biology

Self Cite

View full text Add to dashboard Cite

Cryptosporidiosis, caused by the apicomplexan parasite Cryptosporidium parvum, is a moderate-to-severe diarrheal disease now recognized as one of the leading causes of morbidity and mortality in livestock globally, and in humans living in resource-limited parts of the world, particularly those with AIDS or malnourished individuals. This recognition has fueled efforts for the discovery of effective therapeutics. While recent progress in drug discovery has been encouraging, there are presently no acceptably effective parasite-specific drugs for the disease. The urgent need for new drug discovery or drug repurposing has also increased the need for refined animal models of clinical disease for therapeutic efficacy evaluation. Here, we describe an acute model of cryptosporidiosis using newborn calves to evaluate well-defined clinical and parasitological parameter outcomes, including the effect on diarrhea severity and duration, oocyst numbers produced, and multiple measures of clinical health. The model is highly reproducible and provides unequivocal direct measures of treatment efficacy on diarrhea severity and parasite replication.

show abstract

Advances in bumped kinase inhibitors for human and animal therapy for cryptosporidiosis

Cited by 30 publications

References 30 publications

Comparative assessment of the effects of bumped kinase inhibitors on early zebrafish embryo development and pregnancy in mice

Comparative assessment of the effects of bumped kinase inhibitors on early zebrafish embryo development and pregnancy in mice

Therapeutic Efficacy of Bumped Kinase Inhibitor 1369 in a Pig Model of Acute Diarrhea Caused by Cryptosporidium hominis

Calf Clinical Model of Cryptosporidiosis for Efficacy Evaluation of Therapeutics

Contact Info

Product

Resources

About