About: Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro

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About: Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro
Creator	Joachim, Anja Choi, Ryan Hemphill, Andrew Koston, Florian Ruttkowski, Bärbel Shrestha, Aruna Barrett, Kayleigh Barrett, Lynn Dorr, Carlie Hulverson, Matthew Maly, Dustin Michaels, Samantha Navaluna, Edelmar Ojo, Kayode Van Voorhis, Wesley Vidadala, Rama Whitman, Grant
Source	Elsevier; Medline; PMC
abstract	Cystoisosporosis is a leading diarrheal disease in suckling piglets. With the confirmation of resistance against the only available drug toltrazuril, there is a substantial need for novel therapeutics to combat the infection and its negative effects on animal health. In closely related apicomplexan species, bumped kinase inhibitors (BKIs) targeting calcium-dependent protein kinase 1 (CDPK1) were shown to be effective in inhibiting host-cell invasion and parasite growth. Therefore, the gene coding for Cystoisospora suis CDPK1 (CsCDPK1) was identified and cloned to investigate activity and thermal stabilization of the recombinant CsCDPK1 enzyme by BKI 1369. In this comprehensive study, the efficacy, safety and pharmacokinetics of BKI 1369 in piglets experimentally infected with Cystoisospora suis (toltrazuril-sensitive, Wien-I and toltrazuril-resistant, Holland-I strains) were determined in vivo and in vitro using an established animal infection model and cell culture, respectively. BKI 1369 inhibited merozoite proliferation in intestinal porcine epithelial cells-1 (IPEC-1) by at least 50% at a concentration of 40 nM, and proliferation was almost completely inhibited (>95%) at 200 nM. Nonetheless, exposure of infected cultures to 200 nM BKI 1369 for five days did not induce structural alterations in surviving merozoites as confirmed by transmission electron microscopy. Five-day treatment with BKI 1369 (10 mg/kg BW twice a day) effectively suppressed oocyst excretion and diarrhea and improved body weight gains in treated piglets without obvious side effects for both toltrazuril-sensitive, Wien-I and resistant, Holland-I C. suis strains. The plasma concentration of BKI 1369 in piglets increased to 11.7 μM during treatment, suggesting constant drug accumulation and exposure of parasites to the drug. Therefore, oral applications of BKI 1369 could potentially be a therapeutic alternative against porcine cystoisosporosis. For use in pigs, future studies on BKI 1369 should be directed towards ease of drug handling and minimizing treatment frequencies.
has issue date	2019-04-02(xsd:dateTime)
bibo:doi	10.1016/j.ijpddr.2019.03.004
bibo:pmid	30959327
has license	cc-by
sha1sum (hex)	075c0ee81918f2e0158b9e1807c0a588f3e3949c
schema:url	https://doi.org/10.1016/j.ijpddr.2019.03.004
resource representing a document's title	Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro
has PubMed Central identifier	PMC6453670
has PubMed identifier	30959327
schema:publication	Int J Parasitol Drugs Drug Resist
resource representing a document's body	covid:075c0ee81918f2e0158b9e1807c0a588f3e3949c#body_text
is schema:about of	named entity 'obvious' named entity 'BKI' named entity 'therapeutics' named entity 'porcine' named entity 'activity' named entity 'infected' named entity 'infection' named entity 'gains' named entity 'Cystoisospora' named entity 'effective' named entity 'BKI 1369' named entity 'PLASMA CONCENTRATION' named entity 'GENE' named entity 'PARASITE' named entity 'EPITHELIAL CELLS' named entity 'INCREASED' named entity 'DURING TREATMENT' named entity 'FIVE-DAY' named entity 'INFECTION MODEL' named entity 'CULTURES' named entity 'LEADING' named entity 'NEED FOR' named entity 'HANDLING' named entity 'SIDE EFFECTS' named entity 'IMPROVED' covid:arg/075c0ee81918f2e0158b9e1807c0a588f3e3949c named entity 'ORAL' named entity 'EXPOSURE' named entity 'INFECTION' named entity 'FREQUENCIES' named entity 'MEROZOITE' named entity 'ACCUMULATION' named entity '200' named entity 'TREATED' named entity 'DIARRHEAL DISEASE' named entity 'CYSTOISOSPOROSIS' named entity 'SAFETY' named entity 'CLONED' named entity 'IDENTIFIED' named entity 'STABILIZATION' named entity 'BODY WEIGHT' named entity 'FUTURE' named entity 'IN VIVO' named entity 'RESISTANT' named entity 'SPECIES' named entity 'TREATMENT' named entity 'RECOMBINANT' named entity 'ENZYME' named entity 'DIARRHEA' named entity 'KINASE INHIBITORS' named entity 'DRUG' named entity 'PHARMACOKINETICS' named entity 'APICOMPLEXAN' named entity 'TARGETING' named entity 'EFFECTS' named entity 'PIGS' named entity 'WIEN' named entity 'THERMAL' named entity 'INFECTED' named entity 'CONFIRMED BY' named entity 'RESISTANCE' named entity 'USE' named entity 'ANIMAL' named entity 'MG%' named entity 'EFFECTIVE'

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