Cyclic Peptide Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Design, Synthesis, and In Vivo Treatment of Acute Lung Injury.

Directly blocking the Keap1-Nrf2 pathway is a promising strategy for the mitigation of acute lung injury (ALI). Peptide Keap1-Nrf2 inhibitors have been reported to have a high Keap1 binding affinity. However, these inhibitors showed weak activity in cells and/or animals. In this study, we designed a series of linear peptides from an Nrf2-based 9-mer Ac-LDEETGEFL-NH2. To improve the cellular activity, we further designed cyclic peptides based on the crystal complex of Keap1 with a linear peptide. Among them, cyclic 9-mer ZC9 targeting Keap1 showed a better affinity (KD2 = 51 nM). Specifically, it exhibited an acceptable water solubility (>38 mg/mL), better cell permeability, cell activity, and metabolic stability (serum t1/2 > 24 h). In the in vitro LPS-induced oxidative damages and ALI model, ZC9 showed significant dose-response reversal activity without apparent toxicity. In conclusion, our results suggested ZC9 as a lead cyclic peptide targeting the Keap1-Nrf2 pathway for ALI clinical treatment.

Discovery of novel oridonin sulfamide derivatives as potent NLRP3 inhibitors by a visible-light photocatalysis-enabled peripheral editing.

The progress of organicsyntheticmethod can promote late-stage lead compound modification and novel active compound discovery. Molecular editing technology in the field of organic synthesis, including peripheral and skeletal editing, facilitates rapid access to molecular diversity of a lead compound. Peripheral editing of CH bond activation is gradually used in lead optimization to afford novel active scaffolds and chemical space exploitation. To develop oridonin derivatives with high anti-inflammatory potency, novel oridonin sulfamides had been designed and synthesized by a scaffoldhopping strategy based on a visible-light photocatalysis peripheral editing. All novel compounds revealed measurable inhibition of IL-1ß and low cytotoxicity in THP-1 cells. The docking study indicated that the best active compound ZM640 was accommodated in thebinding site of NLRP3 with two hydrogen bond interaction. These preliminary results confirm that α, ß-unsaturated carbonyl of oridonin is not essential for NLRP3 inhibitory effect. This new oridonin scaffold has its potential to be further developed as a promising class of NLRP3 inhibitors.

SNP within the bovine ASB-3 gene and their association analysis with stature traits in three Chinese cattle breeds.

ASB-3 is one of the 18 members of ASB gene family. As a special negative regulation factor of TNF-R2, ASB-3 inhibits the signal transduction of JNK-TNF-R2 and JNK-STAT signaling pathway by TNF-R2 protein. In this study, the genetic polymorphisms of ASB-3 were detected in total of 637 from Qinchuan, Jinnan and Xianan cattle using the sequence of mixed DNA pool, Tetra-primer ARMS-PCR and PCR-RFLP methods. Four mutation sites were detected including the g.C41255T, g.G74754A, and g.T75438C were synonymous mutation, whereas the g.C115213T was missense mutation (Pro > Ser). The associated analysis of four polymorphic loci of ASB-3 gene respectively with growth traits in the three cattle breeds. The result showed that SNP1 site was significantly related with Qinchuan cattle height and TT was the dominant genotype; SNP2 had a significant relationship with body length of Xianan cattle and cross department height of Qinchuan cattle, AA was the dominant genotype; SNP3 was significantly related to cross height of Xianan cattle, TT was the dominant genotype; SNP4 site was significantly correlated with body height of Xianan cattle and cross height of Jinnan cattle. Genotype combinations were only significantly correlated with the hucklebone width in the adult Qinchuan cattle. The combination genotype CTAGCTCC was outperformed other combination genotypes of Qinchuan cattle. The results showed that ASB-3 could be an important candidate gene and the four SNPs in ASB-3 can be used for molecular marker-assisted selection of four beef cattle breeds.