Structure - Function relationships for inhibitors of β-Amyloid toxicity containing the recognition sequence KLVFF

Tao Lowe, A. Strzelec, L. L. Kiessling, R. M. Murphy

Research output: Contribution to journalArticle

159 Citations (Scopus)

Abstract

β-Amyloid (Aβ), the primary protein component of Alzheimer's plaques, is neurotoxic when aggregated into fibrils. We have devised a modular strategy for generating compounds that inhibit Aβ toxicity. These compounds contain a recognition element, designed to bind to Aβ, linked to a disrupting element, designed to interfere with Aβ aggregation. On the basis of this strategy, a hybrid peptide was synthesized with the sequence KLVFF (residues 16 - 20 of Aβ) as the recognition element and a lysine hexamer as the disrupting element; this compound protects cells in vitro from Aβ toxicity [Pallitto, M. M., et al. (1999) Biochemistry 38, 3570]. To determine if the length of the disrupting element could be reduced, peptides were synthesized that contained the KLVFF recognition element and a sequence of one to six lysines as disrupting elements. All compounds enhanced the rate of aggregation of Aβ, with the magnitude of the effect increasing as the number of lysines in the disrupting element increased. The greatest level of protection against Aβ toxicity was achieved with compounds containing disrupting elements of three or more lysines in sequence. A peptide with an anionic disrupting element, KLVFFEEEE, had activity similar to that of KLVFFKKKK, in both cellular toxicity and biophysical assays, whereas a peptide with a neutral polar disrupting element, KLVFFSSSS, was ineffective. Protective compounds retained activity even at an inhibitor: Aβ molar ratio of 1:100, making these some of the most effective inhibitors of Aβ toxicity reported to date. These results provide critical insight needed to design more potent inhibitors of Aβ toxicity and to elucidate their mechanism of action.

Original languageEnglish (US)
Pages (from-to)7882-7889
Number of pages8
JournalBiochemistry
Volume40
Issue number26
DOIs
StatePublished - Jul 3 2001

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Amyloid
Lysine
Toxicity
Peptides
Serum Amyloid A Protein
Agglomeration
Biochemistry
amyloid beta-protein (16-20)
Assays
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Structure - Function relationships for inhibitors of β-Amyloid toxicity containing the recognition sequence KLVFF. / Lowe, Tao; Strzelec, A.; Kiessling, L. L.; Murphy, R. M.

In: Biochemistry, Vol. 40, No. 26, 03.07.2001, p. 7882-7889.

Research output: Contribution to journalArticle

Lowe, Tao ; Strzelec, A. ; Kiessling, L. L. ; Murphy, R. M. / Structure - Function relationships for inhibitors of β-Amyloid toxicity containing the recognition sequence KLVFF. In: Biochemistry. 2001 ; Vol. 40, No. 26. pp. 7882-7889.
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