A5101492383- Parasitic Infections and Diagnostics
- Toxoplasma gondii Research Studies
- Pneumocystis jirovecii pneumonia detection and treatment
- Research on Leishmaniasis Studies
- RNA and protein synthesis mechanisms
- Biochemical and Molecular Research
- Synthesis and Biological Evaluation
- Trypanosoma species research and implications
- Amoebic Infections and Treatments
- Coccidia and coccidiosis research
- Mosquito-borne diseases and control
- Drug-Induced Hepatotoxicity and Protection
- Complementary and Alternative Medicine Studies
- Click Chemistry and Applications
- Bioactive Compounds and Antitumor Agents
- Advancements in Transdermal Drug Delivery
- Genomics, phytochemicals, and oxidative stress
- Phytochemistry and biological activity of medicinal plants
- Cassava research and cyanide
- Paraquat toxicity studies and treatments
- Alcohol Consumption and Health Effects
- Antimicrobial Resistance in Staphylococcus
- Radical Photochemical Reactions
- Allelopathy and phytotoxic interactions
- Venomous Animal Envenomation and Studies
Jilin University
2024
University of Washington
2013-2023
Seattle University
2020
Weatherford College
2020
Georgia Gwinnett College
2019
Third Affiliated Hospital of Guangzhou Medical University
2018
Guangzhou Medical University
2018
Guangzhou Institute of Dermatology
2018
National University of Singapore
2016
New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by protozoan parasite Toxoplasma gondii. To this end, we previously developed potent and selective inhibitor (compound 1) gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro vivo. Unfortunately, has human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, consequently presents cardiotoxicity risk. Here, describe...
Cryptosporidiosis, caused by the apicomplexan parasite Cryptosporidium parvum, is a diarrheal disease that has produced large global burden in mortality and morbidity humans livestock. There are currently no consistently effective parasite-specific pharmaceuticals available for this disease. Bumped kinase inhibitors (BKIs) specific calcium-dependent protein kinases (CDPKs) have been shown to reduce infection several parasites having medical veterinary importance, including Toxoplasma gondii,...
There is a substantial need for novel therapeutics to combat the widespread impact caused by Crytosporidium infection. However, there lack of knowledge as which drug pharmacokinetic (PK) characteristics are key generate an in vivo response, specifically whether systemic exposure crucial efficacy. To identify PK properties correlated with efficacy, we generated physiologically based models simulate and gastrointestinal concentrations series bumped kinase inhibitors (BKIs) that have nearly...
Cryptosporidiosis is one of the leading causes moderate to severe diarrhea in children low-resource settings. The therapeutic options for cryptosporidiosis are limited drug, nitazoxanide, which unfortunately has poor activity most needy populations malnourished and HIV-infected persons.
5-Aminopyrazole-4-carboxamide was used as an alternative scaffold to substitute for the pyrazolopyrimidine of a known "bumped kinase inhibitor" create selective inhibitors calcium-dependent protein kinase-1 from both Toxoplasma gondii and Cryptosporidium parvum. Compounds with low nanomolar inhibitory potencies against target enzymes were obtained. The most also exhibited submicromolar activities in T. cell proliferation assays shown be non-toxic mammalian cells.
Cryptosporidium is recognized as one of the main causes childhood diarrhea worldwide. However, current treatment for cryptosporidiosis suboptimal. Calcium flux essential entry in apicomplexan parasites. Calcium-dependent protein kinases (CDPKs) are distinct from mammals, and CDPK1 lack side chains that typically block a hydrophobic pocket kinases. We exploited this to develop bumped kinase inhibitors (BKIs) selectively target CDPK1. have shown several BKIs potently reduce enzymatic activity...
Polygonum multiflorum is an herbal medicine widely employed in China. Hepatotoxicity of the has been well documented, but mechanisms toxicity remain unknown. Emodin (EM) a major constituent herb and reported to be hepatotoxic. The main purpose this study was define metabolic pathways EM order characterize potential reactive intermediates. incubated with rat liver microsomes or human microsomes, followed by LC-MS/MS analysis investigate vitro vivo metabolism EM. As result, three...
We previously discovered compounds based on a 5-aminopyrazole-4-carboxamide scaffold to be potent and selective inhibitors of CDPK1 from T. gondii. The current work, through structure–activity relationship studies, led the discovery (34 35) with improved characteristics over starting inhibitor 1 in terms solubility, plasma exposure after oral administration mice, or efficacy parasite growth inhibition. Compounds 34 35 were further demonstrated more effective than mouse infection model...
Cryptosporidium is a leading cause of pediatric diarrhea worldwide. Currently, there neither vaccine nor consistently effective drug available for this disease. Selective 5-aminopyrazole-4-carboxamide-based bumped-kinase inhibitors (BKIs) are in both vitro and vivo models parvum. Potential cardiotoxicity some BKIs led to the continued exploration 5-aminopyrazole-4-carboxamide scaffold find safe candidates Cryptosporidium. A series newly designed were tested efficacy against C. parvum using...
ABSTRACT Antibiotic-resistant bacteria are widespread and pose a growing threat to human health. New antibiotics acting by novel mechanisms of action needed address this challenge. The bacterial methionyl-tRNA synthetase (MetRS) enzyme is essential for protein synthesis, the type found in Gram-positive substantially different from its counterpart mammalian cytoplasm. Both previously published new selective inhibitors were shown be highly active against with MICs ≤1.3 μg/ml Staphylococcus ,...
Benzbromarone (BBR) is a therapeutically useful uricosuric agent but can also cause acute liver injury. The hepatotoxicity of BBR suggested to be associated with its metabolic activation. Our recent study demonstrated that was metabolized epoxide intermediate(s) by cytochrome P450 3A, and the reactive N-acetylcysteine. objectives present were determine chemical identity interaction protein define association modification induced BBR. Microsomal incubation showed covalently modified...
Fluorination is a well-known strategy for improving the bioavailability of drug molecules. However, its impact on efficacy not easily predicted. On basis inhibitor-bound protein crystal structures, we found beneficial fluorination spot inhibitors targeting methionyl-tRNA synthetase Trypanosoma brucei. In particular, incorporating 5-fluoroimidazo[4,5-b]pyridine into leads to central nervous system and maintained or even improved efficacy.
Diosbulbin B (DIOB), a hepatotoxic furan-containing compound, is primary ingredient in Dioscorea bulbifera L., common herbal medicine. Metabolic activation required for DIOB-induced liver injury. Protein covalent binding of an electrophilic reactive intermediate DIOB considered to be one the key mechanisms cytotoxicity. A bromine-based analytical technique was developed characterize chemical identity interaction protein with DIOB. Cysteine (Cys) and lysine (Lys) residues were found react...
Cryptosporidium parvum calcium-dependent protein kinase 1 (CpCDPK1) is a promising target for drug development against cryptosporidiosis. We report series of low-nanomolar CpCDPK1 5-aminopyrazole-4-carboxamide (AC) scaffold inhibitors that also potently inhibit C. growth in vitro Correlation between anti-CpCDPK1 and inhibition, as previously reported pyrazolopyrimidines, was not apparent. Nonetheless, lead AC compounds exhibited substantial reduction parasite burden the neonatal mouse...
Bumped kinase inhibitors (BKIs) are effective against a variety of apicomplexan parasites. Fifteen BKIs with promising in vitro efficacy Neospora caninum tachyzoites, low cytotoxicity mammalian cells, and no toxic effects non-pregnant BALB/c mice were assessed pregnant mice. Drugs emulsified corn oil applied by gavage for 5 days. Five did not affect pregnancy, five exhibited ~15–35% neonatal mortality compounds caused strong (infertility, abortion, stillbirth pup mortality). Additionally,...
Bumped kinase inhibitors (BKIs) have been shown to be potent of Toxoplasma gondii calcium-dependent protein 1. Pyrazolopyrimidine and 5-aminopyrazole-4-carboxamide scaffold-based BKIs are effective in acute chronic experimental models toxoplasmosis. Through further exploration these 2 scaffolds a new pyrrolopyrimidine scaffold, additional compounds identified that extremely against The vivo efficacy demonstrates the cyclopropyloxynaphthyl, cyclopropyloxyquinoline, 2-ethoxyquinolin-6-yl...
Potent <italic>T. brucei</italic> methionyl-tRNA synthetase inhibitors built on two novel short and rigid linker systems.
Recent advances on the development of bumped kinase inhibitors for treatment cryptosporidiosis have focused 5-aminopyrazole-4-carboxamide scaffold, due to analogs that less hERG inhibition, superior efficacy, and strong in vitro safety profiles. Three compounds, BKI-1770, -1841, -1708, showed efficacy C. parvum infected mice. Both BKI-1770 BKI-1841 had newborn calf model, reducing diarrhea oocyst excretion. However, both compounds caused hyperflexion limbs seen as dropped pasterns. Toxicity...