Recent advances in small molecule Nav 1.7 inhibitors for cancer pain management.

The dorsal root ganglion (DRG) is the primary neuron responsible for transmitting peripheral pain signals to the central nervous system and plays a crucial role in pain transduction. Modulation of DRG excitability is considered a viable approach for pain management. Neuronal excitability is intricately linked to the ion channels on the neurons. The small and medium-sized DRG neurons are chiefly engaged in pain conduction and have high levels of TTX-S sodium channels, with Nav1.7 accounting for approximately 80% of the current. Voltage-gated sodium channel (VGSC or Nav) blockers are vital targets for the management of central nervous system diseases, particularly chronic pain. VGSCs play a key role in controlling cellular excitability. Clinical research has shown that Nav1.7 plays a crucial role in pain sensation, and there is strong genetic evidence linking Nav1.7 and its encoding gene SCN9A gene to painful disorders in humans. Many studies have shown that Nav1.7 plays an important role in pain management. The role of Nav1.7 in pain signaling pathways makes it an attractive target for the potential development of new pain drugs. Meanwhile, understanding the architecture of Nav1.7 may help to develop the next generation of painkillers. This review provides updates on the recently reported molecular inhibitors targeting the Nav1.7 pathway, summarizes their structure-activity relationships (SARs), and discusses their therapeutic effects on painful diseases. Pharmaceutical chemists are working to improve the therapeutic index of Nav1.7 inhibitors, achieve better analgesic effects, and reduce side effects. We hope that this review will contribute to the development of novel Nav1.7 inhibitors as potential drugs.

Exploring the Two Coupled Conformational Changes That Activate the Munc18-1/Syntaxin-1 Complex.

Calcium-dependent synaptic vesicle exocytosis is mediated by SNARE complex formation. The transition from the Munc18-1/syntaxin-1 complex to the SNARE complex is catalyzed by the Munc13-1 MUN domain and involves at least two conformational changes: opening of the syntaxin-1 linker region and extension of Munc18-1 domain 3a. However, the relationship and the action order of the two conformational changes remain not fully understood. Here, our data show that an open conformation in the syntaxin-1 linker region can bypass the requirement of the MUN NF sequence. In addition, an extended state of Munc18-1 domain 3a can compensate the role of the syntaxin-1 RI sequence. Altogether, the current data strongly support our previous notion that opening of the syntaxin-1 linker region by Munc13-1 is a key step to initiate SNARE complex assembly, and consequently, Munc18-1 domain 3a can extend its conformation to serve as a template for association of synaptobrevin-2 and syntaxin-1.

Glycine Decarboxylase Expression Increased in p53-Mutated B Cell Lymphoma Mice.

BACKGROUND: p53 gene mutations are associated with human tumors, and are among the most common genetic abnormalities. To understand the relationship between p53 mutations and glycine decarboxylase (GLDC) expression in B cell lymphoma, we established B cell lymphoma animal models to study GLDC expression in B cell lymphoma mice. MATERIALS AND METHODS: Based on immunohistochemical staining results, BALB/c nude mice were divided into a p53 protein-positive group and a p53 protein-negative group. GLDC mRNA expression was determined by real-time polymerase chain reaction, and GLDC protein expression was determined by Western blot. We designed a GLDC-specific interference fragment siRNA-transfected human B cell lymphoma cell line (Raji) to establish a B cell lymphoma animal model. RESULTS: The results showed both GLDC mRNA and protein expression increased in the B cell lymphoma tissue of the p53 protein-positive group compared with the p53 protein-negative group. The proliferation ability of GLDC siRNA-transfected cells decreased significantly compared with the negative-control siRNA group and the blank control group (p < 0.05), which showed that the GLDC gene can promote cell proliferation in p53-mutated B cell lymphoma. CONCLUSION: These studies support a direct relationship between p53 mutations and GLDC expression in B cell lymphoma. GLDC can induce dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism and tumor development.