Chlorinated Naringenin Analogues as Potential Inhibitors of Transthyretin Amyloidogenesis

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.

Automated summary

A naringenin derivative with chlorine atoms was found to effectively prevent the aggregation of transthyretin in the eye, exhibiting amyloid inhibitory activity comparable to tafamidis. X-ray crystal structures showed the binding modes of the derivatives to transthyretin, and ex vivo assays demonstrated their potent binding in plasma relative to tafamidis. In vivo pharmacokinetic studies confirmed significant delivery of the dichlorinated derivative to the eye.