Misfolding and aggregation of transthyretin
are implicated in the
fatal systemic disease known as transthyretin amyloidosis. Here, we
report the development of a naringenin derivative bearing two chlorine
atoms that will be efficacious for preventing aggregation of transthyretin
in the eye. The amyloid inhibitory activity of the naringenin derivative
was as strong as that of tafamidis, which is the first therapeutic
agent targeting transthyretin in the plasma. X-ray crystal structures
of the compounds in complex with transthyretin demonstrated that the
naringenin derivative with one chlorine bound to the thyroxine-binding
site of transthyretin in the forward mode and that the derivative
with two chlorines bound to it in the reverse mode. An ex vivo competitive
binding assay showed that naringenin derivatives exhibited more potent
binding than tafamidis in the plasma. Furthermore, an in vivo pharmacokinetic
study demonstrated that the dichlorinated derivative was significantly
delivered to the eye.
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