Extended-spectrum antiprotozoal bumped kinase inhibitors: A review

Voorhis, Wesley C. Van; Doggett, J. Stone; Parsons, Marilyn; Hulverson, Matthew A.; Choi, Ryan; Arnold, Samuel; Riggs, Michael W.; Hemphill, Andrew; Howe, Daniel K.; Mealey, Robert H.; Lau, Audrey O.T.; Merritt, E.A.; Maly, Dustin J.; Fan, Erkang; Ojo, Kayode K.

doi:10.1016/j.exppara.2017.01.001

Cited by 58 publications

(54 citation statements)

References 111 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Selected bumped kinase inhibitors (BKIs) have a high specific affinity for CpCDPK1. In a previous study, BKI 1294 exhibited inhibitory activity against C. parvum in immunodeficient mice and calves (10,11), and it reduced parasite and disease burdens of C. hominis in the gnotobiotic (GB) piglet model of acute diarrhea (unpublished data). However, it was reported to have cardiotoxicity (10), and consequently, other BKI derivatives were generated and evaluated.…”

mentioning

confidence: 78%

See 1 more Smart Citation

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

mentioning

confidence: 78%

“…BKIs targeting CpCDPK1 do not significantly inhibit mammalian protein kinases and are not known to be toxic to the host (10). Representative BKIs, including BKI 1294 and BKI 1369, were shown to considerably improve the clinical outcome of diarrhea as well as reduce oocyst fecal output in the calf model of C. parvum cryptosporidiosis (11,13).…”

Section: Discussionmentioning

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

show abstract

“…In humans, congenital toxoplasmosis causes fetal malformations and abortion, and recrudescence of latent infection or new infections in immune-suppressed individuals can cause acute toxoplasmosis, with potentially lethal outcomes [4]. Calcium-dependent protein kinase 1 (CDPK1) has emerged as an important drug target in apicomplexans [5]. Homologues of CDPK1 are not present in mammals, but appear to have descended from the plant kingdom [6].…”

Section: Introductionmentioning

confidence: 99%

“…A promising group of compounds are bumped kinase inhibitors (BKIs), which target CDPK1. CDPK1 is structurally similar in many apicomplexans [5]. The high degree of efficacy and specificity of BKIs in apicomplexans relative to mammalian kinases is due to differences in the topology of a hydrophobic pocket within the ATP binding site that is, in part, determined by the size of their respective gatekeeper residues [9].…”

Section: Introductionmentioning

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

“…CDPK1 activity is essential for microneme secretion, host cell invasion, and egress of T. gondii (18,22,23) and can be selectively targeted by a class of ATP-competitive compounds, collectively named bumped kinase inhibitors (BKIs). BKIs have broad-spectrum activity that affects many apicomplexan parasites (24). BKI-1294 is effective against T. gondii in vitro (25) and in vivo against acute (26,27) and chronic (26) toxoplasmosis in mice, as well as against vertical transmission in a pregnant mouse model of toxoplasmosis (28).…”

mentioning

confidence: 99%

Treatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during Pregnancy

Sánchez-Sánchez

Ferre

et al. 2019

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Previous studies on drug efficacy showed low protection against abortion and vertical transmission of Toxoplasma gondii in pregnant sheep. Bumped kinase inhibitors (BKIs), which are ATP-competitive inhibitors of calcium-dependent protein kinase 1 (CDPK1), were shown to be highly efficacious against several apicomplexan parasites in vitro and in laboratory animal models. Here, we present the safety and efficacy of BKI-1294 treatment (dosed orally at 100 mg/kg of body weight 5 times every 48 h) initiated 48 h after oral infection of sheep at midpregnancy with 1,000 TgShSp1 oocysts. BKI-1294 demonstrated systemic exposure in pregnant ewes, with maximum plasma concentrations of 2 to 3 M and trough concentrations of 0.4 M at 48 h after each dose. Oral administration of BKI-1294 in uninfected sheep at midpregnancy was deemed safe, since there were no changes in behavior, fecal consistency, rectal temperatures, hematological and biochemical parameters, or fetal mortality/morbidity. In ewes infected with a T. gondii oocyst dose lethal for fetuses, BKI-1294 treatment led to a minor rectal temperature increase after infection and a decrease in fetal/lamb mortality of 71%. None of the lambs born alive in the treated group exhibited congenital encephalitis lesions, and vertical transmission was prevented in 53% of them. BKI-1294 treatment during infection led to strong interferon gamma production after cell stimulation in vitro and a low humoral immune response to soluble tachyzoite antigens but high levels of anti-SAG1 antibodies. The results demonstrate a proof of concept for the therapeutic use of BKI-1294 to protect ovine fetuses from T. gondii infection during pregnancy.

show abstract

Extended-spectrum antiprotozoal bumped kinase inhibitors: A review

Cited by 58 publications

References 111 publications

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

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

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

Treatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during Pregnancy

Contact Info

Product

Resources

About