Structure-function relationships for inhibitors of beta-amyloid toxicity containing the recognition sequence KLVFF

beta -Amyloid (A beta), the primary protein component of Alzheimer's plaque s, is neurotoxic when aggregated into fibrils. We have devised a modular st rategy for generating compounds that inhibit A beta toxicity. These compoun ds contain a recognition element, designed to bind to A beta, linked to a d isrupting element, designed to interfere with A beta aggregation. On the ba sis of this strategy, a hybrid peptide was synthesized with the sequence KL VFF (residues 16-20 of A beta) as the recognition element and a lysine hexa mer as the disrupting element: this compound protects cells in vitro from A beta toxicity [Pallitto, M. M., et al. (1999) Biochemistry 38, 3570]. To d etermine if the length of the disrupting element could be reduced, peptides were synthesized that contained the KLVFF recognition element and a sequen ce of one to six lysines as disrupting elements. All compounds enhanced the rate of aggregation of A beta, with the magnitude of the effect increasing as the number of lysines in the disrupting element increased. The greatest level of protection against A beta toxicity was achieved with compounds co ntaining disrupting elements of three or mole lysines in sequence. A peptid e with an anionic disrupting element, KLVFFEEEE, had activity similar to th at of KLVFFKKKK, in both cellular toxicity and biophysical assays, whereas a peptide with a neutral polar disrupting element, KLVFFSSSS, was ineffecti ve. Protective compounds retained activity even at an inhibitor:A beta mola r ratio of 1:100, making these some of the most effective inhibitors of A b eta toxicity reported to date. These results provide critical insight neede d to design more potent inhibitors of A beta toxicity and to elucidate thei r mechanism of action.