Linear and Rationally Designed Stapled Peptides Abrogate TLR4 Pathway and Relieve Inflammatory Symptoms in Rheumatoid Arthritis Rat Model

A mounting evidence exists for the
despicable role of the aberrant
immune response in the pathogenesis of rheumatoid arthritis (RA),
where toll-like receptor 4 (TLR4) can activate synovial fibroblasts
that lead to the chronic inflammation and joint destruction, thus
making TLR4 a potent drug target in RA. We report that novel TLR4-antagonizing
peptide, PIP2, inhibits the induction of inflammatory biomarkers in
vitro as well as in vivo. Systemically, PIP2 inhibits the lipopolysaccharide
(LPS)-elicited TNF-α, IL-6, and IL-12p40 in a mouse model. The
rationally designed cyclic derivative, cPIP2, is capable of inhibiting
LPS-induced proinflammatory cytokines at significantly lower concentration
as compared to PIP2 (PIP2 IC50 = 20 μM, cPIP2 IC50 = 5 μM). Finally, cPIP2 was able to relieve the inflammatory
symptoms and synovial tissue destruction in the RA rat model. Cumulatively,
these data suggest that PIP2 and cPIP2 hold strong promise for the
development of peptide-based immunotherapeutics that could be of great
value in curbing TLR-related immune complications including RA.