Novel inhibitors against Cryptosporidium parvum through blocking its energy metabolism
- 1College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, PR China.
- 2College of Sciences, Nanjing Agricultural University, Nanjing, PR China.
Abstract
Through systematic structural optimization and modification of anti-Cryptosporidium parvum compound NSC158011 (N-1-naphthalenyl-2-(phenylthiol) ethane thioamide), we constructed a virtual compound library comprising 1,440 derivatives, and 29 derivatives were selected via molecular docking for chemical synthesis. Among them, eight derivatives exhibited significant inhibitory effects on LDH compared with NSC158011. In vitro examination found that two derivatives could markedly reduce the number of C. parvum in cells while exhibiting reduced toxicity. In vivo studies in model animals (IFN-γ knockout mouse) and native animals (calves) further validated the derivatives’ potent anti-parasitic effects and their ability to alleviate intestinal villus atrophy caused by parasitic infections. Further investigations revealed that compound treatment was associated with upregulated expression of intestinal tight junction proteins (ZO-1, Occludin, Claudin-1) and downregulated the expression level of inflammatory protein Caspase-1. Analysis of the gut microbiota and metabolomics in calves indicated that treatment significantly restored the abundance of beneficial flora and regulated key metabolites, including isocitric acid and ornithine. The two derivatives identified in this study represent promising lead compounds for further development as anti-cryptosporidiosis agents, with potential relevance to livestock production and public health. Author summary: In developing countries, cryptosporidiosis represents one of the leading causes of childhood diarrhea and growth retardation. However, there remains a lack of safe and effective therapeutic options in clinical practice. In this study, we optimized the structure of the lead compound NSC158011 to construct a virtual compound library comprising 1,440 derivatives. The candidate compounds with high affinity for the active site of lactate dehydrogenase (LDH) were screened out by molecular docking and binding free energy calculation for synthesis verification. Two potent antiparasitic derivatives were ultimately identified through high-throughput enzyme kinetics screening, cell assays and animal experiments conducted in two model systems. Further investigation revealed that this therapeutic approach may alleviate mitochondrial dysfunction and enhance energy metabolism and oxidative stress responses by restoring the function of the TCA cycle.
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BibTeX
@article{xu2026novel,
title = {{Novel inhibitors against Cryptosporidium parvum through blocking its energy metabolism}},
author = {Chang Xu and Yaru Ji and Qiang Sha and Kun Li},
journal = {PLOS Neglected Tropical Diseases},
year = {2026},
month = oct,
doi = {10.1371/journal.pntd.0014742},
url = {https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014742},
note = {CC BY},
}
RIS
TY - JOUR
TI - Novel inhibitors against Cryptosporidium parvum through blocking its energy metabolism
AU - Chang Xu
AU - Yaru Ji
AU - Qiang Sha
AU - Kun Li
PY - 2026
DA - 2026/10/05
JO - PLOS Neglected Tropical Diseases
DO - 10.1371/journal.pntd.0014742
UR - https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014742
AB - Through systematic structural optimization and modification of anti-Cryptosporidium parvum compound NSC158011 (N-1-naphthalenyl-2-(phenylthiol) ethane thioamide), we constructed a virtual compound library comprising 1,440 derivatives, and 29 derivatives were selected via molecular docking for chemical synthesis. Among them, eight derivatives exhibited significant inhibitory effects on LDH compared with NSC158011. In vitro examination found that two derivatives could markedly reduce the number of C. parvum in cells while exhibiting reduced toxicity. In vivo studies in model animals (IFN-γ knockout mouse) and native animals (calves) further validated the derivatives’ potent anti-parasitic effects and their ability to alleviate intestinal villus atrophy caused by parasitic infections. Further investigations revealed that compound treatment was associated with upregulated expression of intestinal tight junction proteins (ZO-1, Occludin, Claudin-1) and downregulated the expression level of inflammatory protein Caspase-1. Analysis of the gut microbiota and metabolomics in calves indicated that treatment significantly restored the abundance of beneficial flora and regulated key metabolites, including isocitric acid and ornithine. The two derivatives identified in this study represent promising lead compounds for further development as anti-cryptosporidiosis agents, with potential relevance to livestock production and public health. Author summary: In developing countries, cryptosporidiosis represents one of the leading causes of childhood diarrhea and growth retardation. However, there remains a lack of safe and effective therapeutic options in clinical practice. In this study, we optimized the structure of the lead compound NSC158011 to construct a virtual compound library comprising 1,440 derivatives. The candidate compounds with high affinity for the active site of lactate dehydrogenase (LDH) were screened out by molecular docking and binding free energy calculation for synthesis verification. Two potent antiparasitic derivatives were ultimately identified through high-throughput enzyme kinetics screening, cell assays and animal experiments conducted in two model systems. Further investigation revealed that this therapeutic approach may alleviate mitochondrial dysfunction and enhance energy metabolism and oxidative stress responses by restoring the function of the TCA cycle.
SN - 1935-2735
SN - 1935-2727
ER -