Development of Pyrrole-Imidazole Polyamide Targeting Fc Receptor Common Gamma Chain for the Treatment of Immune-Complex Related Renal Disease

Fc gamma receptors I and III are thought to be involved in the development of lupus nephritis. Expression of Fe receptor common gamma chain (FcR gamma) is necessary for the stable expression of Fc gamma receptors I and Ill. The aim of this study was to develop a novel agent for the treatment of immune complex related renal disease using a gene regulator, pyrrole(Py)-imidazole(Im) (PI) polyamide, targeting the mouse FcR gamma gene promoter. Two PI polyamides targeting FcR gamma promoters were designed and synthesized. The effect of the PI polyamides on FcR gamma mRNA expression was evaluated in J774.A cells by real-time polymerase chain reaction (PCR), and CD16/32 protein expression was determined by immunocytochemical analysis and flow cytometry. The effects of these polyamides on FcR gamma gene expression and CD16/32 protein expression were evaluated in mouse peripheral blood mononuclear cells (PBMCs). One milligram per kilogram body weight of PI polyamide was injected via the tail vein every 2d for I week and PBMCs were collected and analyzed. PI polyamide showed a specific binding to the target DNA in a gel mobility shift assay. Treatment of J774.A cells with 1.0 mu m PI polyamide 1 significantly reduced FcR gamma mRNA expression and CD16/32 surface protein expression in J774.A cells. Similarly, PI polyamide significantly decreased expression of FcR gamma mRNA and CD16/32 in the PBMCs of C57B6 mice. PI polyamide designed to bind the FcR gamma promoter decreased FcR gamma gene and CD16/32 protein expression. PI polyamide targeting the FcR gamma gene may be a novel gene regulator for the prevention of lupus nephritis or other immune complex-related disease.