Peptide allosteric inhibitor of TNFR1 signaling attenuates inflammation and rheumatoid arthritis pathology in human TNF transgenic mice

Inhibition of tumor necrosis factor receptor 1 (TNFR1) represents a major therapeutic strategy for chronic autoimmune and inflammatory diseases such as rheumatoid arthritis (RA). As current anti-TNF therapies can cause adverse side effects due to global blockade of the ligand, receptor-specific inhibition of TNFR1 signaling has emerged as a highly sought-after strategy. We have recently identified a novel peptide-based allosteric inhibitor, FKC (FKCRRWQWRMKK), that targets TNFR1 conformationally active region to alter receptor conformational states and disable receptor-ligand signaling complex. Here, we evaluated the therapeutic efficacy of FKC in a human TNF (hTNF) transgenic mouse model of RA. FKC treatment improves clinical RA scores in hTNF mice, accompanied by enhanced grip strength and increased walking distance. Importantly, FKC treatment inhibits TNF/TNFR1-mediated inflammation and attenuates RA pathology in hTNF mice. Together, our findings establish FKC as a promising new class of peptide-based therapeutics for chronic inflammatory diseases through selective inhibition of TNFR1 signaling.