Introduction
Delmitide, also known as RDP58, is a novel D-amino acid decapeptide with anti-inflammatory effect. RDP58 is a ten D-amino acid peptide with the sequence of 2HN-r-nle-nle-nle-r-nle-nle-nle-g-y-CONH2, which is developed by computer-aided rational design based on HLA-derived peptides. Meanwhile, RDP58 is discovered to reduce production of the inflammatory cytokines tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, and IL-12 in cell lines, animal models of colitis. More recently, it is shown that RDP58 inhibits TNF synthesis but does not alter tumor necrosis factor (TNF) mRNA expression, which suggests that the peptide acts at a post-transcriptional step. Therefore, RDP58 is a potential peptide for treating inflammatory colitis disease.
Pharmacologic action
TNF plays a key role in the pathogenesis of crohn disease (CD). Delmitide has proved to be a potent inhibitor of TNF production at a post-transcriptional step, which reduces inflammation by targeting the formation of the MyD88/IRAK/TRAF6 protein complex and inhibits synthesis of proinflammatory cytokines by disrupting cell signaling at the pre-MAPK MyD88-IRAK-TRAF6 protein complex. That is to say, when activated by their respective ligands, Toll-like receptors recruit the cytosolic protein MyD88, which functions as an adaptor, recruiting and phosphorylating IRAK to form a complex with TRAF6. It consequently regulates the phosphorylation and activates the transcription factors AP1 and NF-кB and activates stress-activated protein kinases p38 and JNK. At the same time, it inhibits early signal transduction pathways for the expression of inflammatory cytokines and upregulates heme oxygenase-1.
Function
RDP58 leads to decreased IFN-γ and TNF production by biopsies and lamina propria mononuclear cells from CD patients. At the same time, in rats with TNBS-induced colitis, oral RDP58 therapy reduces diarrhoea and weight loss, improves histological and macroscopic inflammation scores. Furthermore, RDP58 significantly reduces chronic, acute and total inflammation scores and enhances re-epithelialization by reducing crypt scores. In a large number of animal models, RDP58 effectively decreases TNF-α expression and inflammation, at very low doses, and without undue toxic effects, which demonstrates that RDP58 provides a novel and promising method of treating inflammatory bowel disease (IBD). Moreover, RDP58 is not bioavailable and is well tolerated.
Pharmacokinetics and metabolism
The bioavailibility, pharamcokinetics, tissue distribution and excretion of RDP58 after oral administration were studied in dogs and mice, the results indicated that there is little or no systemic absorption of the peptide in dogs and mice with irritated or non-irritated gastrointestinal tract. In addition, RDP58 is safe and well tolerated, and its novel action makes it an attractive potential therapy.
References:
1. Travis, S., Yap, L. M., Hawkey, C., Warren, B., Lazarov, M., Fong, T., & Tesi, R. J. (2005). RDP58 is a novel and potentially effective oral therapy for ulcerative colitis. Inflammatory bowel diseases, 11(8), 713-719.
2. Bourreille, A., Doubremelle, M., de la Blétière, D. R., Segain, J. P., Toquet, C., Buelow, R., & Galmiche, J. P. (2003). RDP58, a novel immunomodulatory peptide with anti-inflammatory effects. A pharmacological study in trinitrobenzene sulphonic acid colitis and Crohn disease. Scandinavian journal of gastroenterology, 38(5), 526-532.
3.Murthy, S., Flanigan, A., Coppola, D., & Buelow, R. (2002). RDP58, a locally active TNF inhibitor, is effective in the dextran sulphate mouse model of chronic colitis. Inflammation Research, 51(11), 522-531.
