Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system that is characterised by the loss of oligodendrocytes, myelin, and axonal degeneration. It is the leading cause of non-traumatic neurological disorder in young adults, to which there is currently no cure. While current treatments reduce the frequency of relapses, they are largely insufficient at preventing the accumulation of permanent disability. An alternate strategy that has recently been explored is remyelination as a form of neuroprotection.
Transthyretin (TTR) has emerged as a potential therapeutic target for the treatment of demyelinating diseases such as multiple sclerosis. Recent studies have revealed that TTR-null mice exhibit a hyper-myelination phenotype, synchronous with increased number of oligodendrocytes [1,2]. The objective of this research was to establish a hit series of small molecules that bind to human-TTR that could be developed into novel treatments for demyelinating diseases.
To identify potential compounds, we utilized structure-based drug design to identify chemically similar analogues of small molecules which have previously been shown to bind to recombinant-hTTR (unpublished). Overall, we have established two series of small molecules that bind to recombinant-hTTR with high affinity (>20 µM) using surface plasmon resonance, display no significant cytotoxicity in a HEK-293 cell culture, and we have begun mapping the binding modes of these small molecules using X-ray crystallography.