Anti-REL monoclonal antibody, clone 429DU52.4.3

Autoimmune diseases are a physiological state that immune responses are directed against and damage the body's own tissues. Numerous studies have demonstrated promising therapeutic effects in certain autoimmune diseases by targeting IL-23/IL-17 axis, mostly through using Abs against IL-23 or IL-17A. Pyrrole-imidazole polyamides are nuclease-resistant compounds that inhibit gene expression through binding to the minor groove of DNA. To develop a novel gene-silencing agent that targets IL-23/IL-17 axis, we designed polyamide that specifically binds to the transcription factor c-Rel-binding site located in the promoter of IL-23p19 subunit. Our study showed that this polyamide is capable of entering into nucleus with high efficiency in dendritic cells and macrophage. In addition, it prevented the binding of c-Rel to the promoter of IL-23p19 in vivo and specifically inhibited the expression of IL-23. More importantly, we demonstrated that this polyamide is therapeutically effective using both the imiquimod-induced psoriasis and experimental autoimmune uveitis mouse models. Taken together, these results indicate that pyrrole-imidazole polyamide targeting IL-23p19 could be a novel and feasible therapeutic strategy for patients with autoimmune diseases.

The stringent response, controlled by (p)ppGpp, enables bacteria to trigger a strong phenotypic resetting that is crucial to cope with adverse environmental changes and is required for stress survival and virulence. In the bacterial cell, (p) ppGpp levels are regulated by the concerted opposing activities of RSH (RelA/ SpoT homologue) enzymes that can transfer a pyrophosphate group of ATP to the 30 position of GDP (or GTP) or remove the 30 pyrophosphate moiety from (p) ppGpp. Bifunctional Rel enzymes are notoriously difficult to crystallize owing to poor stability and a propensity for aggregation, usually leading to a loss of biological activity after purification. Here, the production, biochemical analysis and crystallization of the bifunctional catalytic region of the Rel stringent factor from Thermus thermophilus (Rel(Tt)(NTD)) in the resting state and bound to nucleotides are described. Rel(Tt) and Rel(Tt)(NTD) are monomers in solution that are stabilized by the binding of Mn2+ and mellitic acid. Rel(Tt)(NTD) crystallizes in space group P4(1)22, with unit-cell parameters a = b = 88.4, c = 182.7 angstrom, at 4 degrees C and in space group P4(1)2(1)2, with unit-cell parameters a = b = 105.7, c = 241.4 angstrom, at 20 degrees C.