Novel, small molecule inhibitors of protein aggregation for treatment of amyloid-related diseases

Ab plaque burden. Catalytically incompetent 2E6 treated with a protease inhibitor and a non-proteolytic control IgVL2 did not express these activities. The major 2E6-cleavage site in Ab was the His14-Gln15 peptide bond. Epitope mapping indicated competitive inhibition of 2E6-catalyzed I-Ab degradation by the remote Ab29-40 peptide, identifying this region as the noncovalent recognition epitope. 2E6-Ab immune complexes were undetectable by ELISA, consistent with rapid progress of the reaction to the catalysis step. 2E6 did not cleave His-Gln containing proteins, indicating that specificity for Ab derives from the noncovalent binding step. Conclusions: The Ab fragment targets monomer and aggregate forms of Ab and clears brain Ab plaques by initial noncovalent recognition of the amyloidogenic C terminal region followed by cleavage at remote peptide bonds. Catalysis is rapid and no immune complexes are detectable. This catalytic antibody fragment can be developed for more effective and safe AD immunotherapy.