Transthyretin amyloidosis (ATTR) is a systemic disease that primarily affects the heart and the peripheral nervous system. Despite available therapeutic options, advanced ATTR amyloidosis still presents unmet medical needs. We have therefore focused on the design of bivalent small molecules starting from our prototype palindromic ligand mds84, whose binding by transthyretin (TTR) greatly improves stability of the native structure by overcoming the negative cooperativity which is typical of monovalent stabilizers. Among the newly designed compounds here, we present B26, which is pseudoirreversibly bound by native TTR with faster entry kinetics into the protein molecule compared to mds84. It retains the ability to inhibit fibril formation in vitro, together with improved solubility. Using solution NMR, we show that B26 occupies both TTR binding sites simultaneously, leading to conformational effects distant from the binding site, including the proteolytic cleavage site involved in fibril formation by the mechano-enzymatic mechanism.