Transthyretin (TTR) is a homotetrameric protein involved in human hereditary
amyloidoses. The discovery and development of small molecules that inhibit the
amyloid fibril formation of TTR is one of the therapeutic strategies for these
diseases. Herein, we discovered that γ-mangostin (γ-M) is an effective
inhibitor against the amyloid fibril formation of V30M amyloidogenic TTR.
In-vitro binding assays revealed that γ-M was the most potent of the selected
xanthone derivatives, and it bound to the thyroxine (T4)-binding sites and
stabilized the TTR tetramer. X-ray crystallographic analysis revealed the
diagonal binding mode of γ-M and the two binding sites of chloride ions at the
T4-binding site. One of the chloride ions was replaced with a water molecule in
the α-mangostin complex, which is a methylated derivative of γ-M. The stronger
inhibitory potency of γ-M could be explained by the additional hydrogen bonds
with the chloride ion. The present study establishes γ-M as a novel inhibitor
of TTR fibrillization.
