Abstract
Rheumatoid arthritis (RA) remains a debilitating autoimmune condition as many patients are refractory to existing conventional and biologic therapies, and hence successful development of novel treatments remains a critical requirement. Towards this, we now describe a synthetic drug-like small molecule analogue, SMA-12b, of an immunomodulatory parasitic worm product, ES-62, which acts both prophylactically and therapeutically against collagen-induced arthritis (CIA) in mice. Mechanistic analysis revealed that SMA-12b modifies the expression of a number of inflammatory response genes, particularly those associated with the inflammasome in mouse bone marrow-derived macrophages and indeed IL-1β was the most down-regulated gene. Consistent with this, IL-1β was significantly reduced in the joints of mice with CIA treated with SMA-12b. SMA-12b also increased the expression of a number of genes associated with anti-oxidant responses that are controlled by the transcription factor NRF2 and critically, was unable to inhibit expression of IL-1β by macrophages derived from the bone marrow of NRF2−/− mice. Collectively, these data suggest that SMA-12b could provide the basis of an entirely novel approach to fulfilling the urgent need for new treatments for RA.
Highlights
Rheumatoid arthritis (RA) is one of the more common inflammatory diseases to affect Western societies with a prevalence rate of 1% [1]
We have recently provided proof of concept that screening of PC-based compounds for their ability to suppress TLR2, TLR4- and TLR9-mediated production of Th1/Th17-promoting cytokines (IL12p40 and IL-6) by macrophages allows the selection of small drug-like PC-based molecular analogues (SMAs), such as the sulfone 11a, that mimic the ability of ES-62 to protect against
The low levels of IL-12p40 spontaneously secreted ex vivo by Draining lymph node (DLN) cells were reduced to levels comparable to those produced by naive cells, in cultures derived from 12b-treated mice undergoing Collagen-induced arthritis (CIA) (Fig. 1H)
Summary
Rheumatoid arthritis (RA) is one of the more common inflammatory diseases to affect Western societies with a prevalence rate of 1% [1]. As a consequence of this, we hypothesized that it could be possible to synthesize novel small drug-like PC-based molecular analogues (SMAs) that mimic ES-62 activity: recently we produced a sulfone termed 11a that protects against CIA and appears to do so using the same mechanism of action as ES-62, namely inhibiting TLR-mediated pro-inflammatory cytokine responses, by partially downregulating MyD88 expression [9]. We describe another novel sulfone, 12b, which inhibits disease development in mice sensitized and challenged with collagen, but which contains additional previously unsuspected immunomodulatory properties. SMA-12b may be prototypic of a novel class of compounds of use in treating RA, in particular in those patients resistant to TNF-targeting biologics [11]
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