Abstract
A simple in vitro assay involving the measurement of IL-6 production in human synovial fibroblasts from rheumatoid arthritis patients has been utilised to select candidates from a targeted library of queuine tRNA ribosyltransferase (QTRT) substrates for subsequent in vivo screening in murine experimental autoimmune encephalomyelitis (EAE - a model of multiple sclerosis). The in vitro activity assay discriminated between poor and excellent 7-deazaguanine QTRT substrates and allowed the identification of several structures which subsequently outperformed the previous lead in EAE. Two molecules were of significant promise: one rigidified analogue of the lead, and another considerably simpler structure incorporating an oxime motif which differs structurally from the lead to a considerable extent. These studies provide data from human cells for the first time and have expanded both the chemical space and current understanding of the structure-activity relationship underpinning the remarkable potential of 7-deazguanines in a Multiple Sclerosis disease model.