Structure-based design and synthesis of anti-fibrotic compounds derived from para-positioned 3,4,5-trisubstituted benzene.

Liver fibrosis is an abnormal wound-healing response to liver injuries. It can lead to liver cirrhosis, and even liver cancer and liver failure. There is a lack of treatment for liver fibrosis and it is of great importance to develop anti-fibrotic drugs. A pivotal event in the process of developing liver fibrosis is the activation of hepatic stellate cells (HSCs), in which the nuclear receptor Nur77 plays a crucial role. This study aimed to develop novel anti-fibrotic agents with Nur77 as the drug target by modifying the structure of THPN, a Nur77-binding and anti-melanoma compound. Specifically, a series of para-positioned 3,4,5-trisubstituted benzene ring compounds with long-chain backbone were generated and tested for anti-fibrotic activity. Among these compounds, compound A8 was with the most potent and Nur77-dependent inhibitory activity against TGF-ß1-induced activation of HSCs. In a crystal structure analysis, compound A8 bound Nur77 in a peg-in-hole mode as THPN did but adopted a different conformation that could interfere the Nur77 interaction with AKT, which was previous shown to be important for an anti-fibrotic activity. In a cell-based assay, compound A8 indeed impeded the interaction between Nur77 and AKT leading to the stabilization of Nur77 without the activation of AKT. In a mouse model, compound A8 effectively suppressed the activation of AKT signaling pathway and up-regulated the cellular level of Nur77 to attenuate the HSCs activation and ameliorate liver fibrosis with no significant toxic side effects. Collectively, this work demonstrated that Nur77-targeting compound A8 is a promising anti-fibrotic drug candidate.

Combined transcriptomics and proteomics to identify differential proteins involved in the immune response to the parasite schistosoma japonicum in snail hosts pre-infected with exorchis sp.

Oncomelania hupensis is the obligate intermediate host of Schistosoma japonicum, and it also serves as the first intermediate host for Exorchis sp., which uses Parasilurus asoyus as its definitive host rather than humans. In previous studies, Tang et al. found that all S. japonicum larvae can be blocked and killed in O. hupensis pre-infected with Exorchis sp. eggs. However, the molecular and cellular mechanisms involved in this process remain unclear. Therefore, in the present study, a combined transcriptomic and proteomic analysis was performed to identify the differential proteins involved in the immune response to the parasite S. japonicum in the O. hupensis snail host pre-infected with Exorchis sp. trematodes. The results showed that a total of 46,162 unigenes were obtained with 23,535 (50.98%) unigenes annotated in relevant databases, and 3811 proteins from O. hupensis were identified. In addition, iTRAQ-based quantitative proteomic analysis demonstrated that among three groups (OhSj-1_vs_OhN-1, OhE-1_vs_OhN-1 and OhES-1_vs_OhN-1), there were 146 common differential proteins including 44 up-regulated proteins and 90 down-regulated proteins, and 195 differential proteins exclusive to only one experimental group, including 91 up-regulated proteins and 104 down-regulated proteins, which were defined as the Common group and the Only group, respectively. KEGG analysis showed that 15 and 11 differential proteins were annotated in "Infectious diseases" in the Common group and the Only group, respectively, indicating that these proteins may be involved in the snail host immune response to parasite infection. These data will be helpful for better understanding the host-parasite interaction, and could pave the way towards exploring the mechanisms involved in the biological control on S. japonicum in O. hupensis. They also provide valuable information about developing new anti-schistosomiasis strategies.

Design, synthesis, and evaluation of a novel macrocyclic anti-EV71 agent.

We describe here the design, synthesis, and evaluation of a macrocyclic peptidomimetic as a potent agent targeting enterovirus A71 (EV71). The compound has a 15-membered macrocyclic ring in a defined conformation. Yamaguchi esterification reaction was used to close the 15-membered macrocycle instead of the typical Ru-catalyzed ring-closing olefin metathesis reaction. The crystallographic characterization of the complex between this compound and its target, 3C protease from EV71, validated the design and paved the way for the generation of a new series of anti-EV71 agents.