BMS906024, a γ-secretase inhibitor that blocks Notch signaling, was previously shown to inhibit Cryptosporidium parvum growth in vitro. A structure-activity relationship (SAR) analysis of BMS906024 reported herein demonstrates the importance of the stereochemistry of the C-3 benzodiazepine and the succinyl β-substituent. However, concomitant removal of the succinyl α-substituent and switching the primary amide with secondary amides was tolerated. For example, 32 (SH287) inhibited C. parvum growth in HCT-8 host cells with an EC = 6.4 nM and an EC = 16 nM; however, blocking C. parvum growth with BMS906024 derivatives was correlative with inhibition of Notch signaling, highlighting that additional SAR analysis will be needed to separate these two activities.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10290938 | PMC |
| http://dx.doi.org/10.1016/j.bmcl.2023.129328 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
(E)-2-Octenal inhibits Neofusicoccum parvum growth by disrupting mitochondrial energy metabolism and is a potential preservative for postharvest mango.
Food Res Int
February 2025
School of Chemical Engineering, Xiangtan University, Xiangtan 411105, China. Electronic address:
Stem-end rot caused by Neofusicoccum parvum is among the most detrimental diseases affecting postharvest mangoes. The present investigation utilized (E)-2-octenal to manage N. parvum infections, elucidating its mechanism of action.
View Article and Find Full Text PDFStage-specific expression and divergent functions of two insulinase-like proteases associated with host infectivity in Cryptosporidium.
PLoS Negl Trop Dis
January 2025
State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, China.
Background: The determinants of differences in host infectivity among Cryptosporidium species and subtypes are poorly understood. Results from recent comparative genomic studies suggest that gains and losses of multicopy subtelomeric genes encoding insulinase-like proteases (INS-19 and INS-20 in Cryptosporidium parvum and their orthologs in closely related species) may potentially contribute to these differences.
Methodology/principal Findings: In this study, we investigated the expression and biological function of the INS-19 and INS-20 of C.
Structure guided modification of 2-chloro-5-(ethyl-phenyl-sulfamoyl)-N-[2-(2-oxo-pyrrolidin-1-yl)-phenyl]-benzamide to afford selective inhibitors of Cryptosporidium parvum N-myristoyltransferase.
Bioorg Med Chem Lett
January 2025
Department of Biochemistry, University of Washington, Seattle, WA 98195, United States. Electronic address:
Cryptosporidium parvum is a protozoan parasite that causes severe diarrheal illness in children and each year nearly 50,000 children under age 5 die due to the disease. Despite tremendous research efforts, there remains a lack of effective therapies and vaccines. Novel inhibitors against N-myristoyltransferase of C.
View Article and Find Full Text PDFProgression of the faecal microbiome in preweaning dairy calves that develop cryptosporidiosis.
Anim Microbiome
January 2025
School of Pharmacy and Life Sciences, Robert Gordon University, Garthdee Road, Aberdeen, AB10 7GJ, UK.
Background: Cryptosporidiosis is a diarrheal disease that commonly affects calves under 6 weeks old. The causative agent, Cryptosporidium parvum, has been associated with the abundance of specific taxa in the faecal microbiome during active infection. However, the long-term impact of these microbiome shifts, and potential effects on calf growth and health have not yet been explored in depth.
View Article and Find Full Text PDFMulticopy subtelomeric genes underlie animal infectivity of divergent Cryptosporidium hominis subtypes.
Nat Commun
December 2024
State Key Laboratory for Animal Disease Control and Prevention, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
The anthroponotic Cryptosporidium hominis differs from the zoonotic C. parvum in its lack of infectivity to animals, but several divergent subtypes have recently been found in nonhuman primates and equines. Here, we sequence 17 animal C.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!