Inhibition of β-Amyloid(40) Fibrillogenesis and Disassembly of β-Amyloid(40) Fibrils by Short β-Amyloid Congeners Containing N-Methyl Amino Acids at Alternate Residues
A potential goal in the prevention or therapy of Alzheimer's disease is to decrease or eliminate neuritic plaques composed of fibrillar β-amyloid (Aβ). In this paper we describe N-methyl amino acid containing congeners of the hydrophobic “core domain” of Aβ that inhibit the fibrillogenesis of f...
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description | A potential goal in the prevention or therapy of Alzheimer's disease is to decrease or eliminate neuritic plaques composed of fibrillar β-amyloid (Aβ). In this paper we describe N-methyl amino acid containing congeners of the hydrophobic “core domain” of Aβ that inhibit the fibrillogenesis of full-length Aβ. These peptides also disassemble preformed fibrils of full-length Aβ. A key feature of the inhibitor peptides is that they contain N-methyl amino acids in alternating positions of the sequence. The most potent of these inhibitors, termed Aβ16−22m, has the sequence NH2-K(Me-L)V(Me-F)F(Me-A)E-CONH2. In contrast, a peptide, NH2-KL(Me-V)(Me-F)(Me-F)(Me-A)-E-CONH2, with N-methyl amino acids in consecutive order, is not a fibrillogenesis inhibitor. Another peptide containing alternating N-methyl amino acids but based on the sequence of a different fibril-forming protein, the human prion protein, is also not an inhibitor of Aβ40 fibrillogenesis. The nonmethylated version of the inhibitor peptide, NH2-KLVFFAE-CONH2 (Aβ16−22), is a weak fibrillogenesis inhibitor. Perhaps contrary to expectations, the Aβ16−22m peptide is highly soluble in aqueous media, and concentrations in excess of 40 mg/mL can be obtained in buffers of physiological pH and ionic strength, compared to only 2 mg/mL for Aβ16−22. Analytical ultracentrifugation demonstrates that Aβ16−22m is monomeric in buffer solution. Whereas Aβ16−22 is susceptible to cleavage by chymotrypsin, the methylated inhibitor peptide Aβ16−22m is completely resistant to this protease. Circular dichroic spectroscopy of Aβ16−22m indicates that this peptide is a β-strand, albeit with an unusual minimum at 226 nm. In summary, the inhibitor motif is that of alternating N-methyl and nonmethylated amino acids in a sequence critical for Aβ40 fibrillogenesis. These inhibitors appear to act by binding to growth sites of Aβ nuclei and/or fibrils and preventing the propagation of the network of hydrogen bonds that is essential for the formation of an extended β-sheet fibril. |
doi_str_mv | 10.1021/bi002416v |
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In this paper we describe N-methyl amino acid containing congeners of the hydrophobic “core domain” of Aβ that inhibit the fibrillogenesis of full-length Aβ. These peptides also disassemble preformed fibrils of full-length Aβ. A key feature of the inhibitor peptides is that they contain N-methyl amino acids in alternating positions of the sequence. The most potent of these inhibitors, termed Aβ16−22m, has the sequence NH2-K(Me-L)V(Me-F)F(Me-A)E-CONH2. In contrast, a peptide, NH2-KL(Me-V)(Me-F)(Me-F)(Me-A)-E-CONH2, with N-methyl amino acids in consecutive order, is not a fibrillogenesis inhibitor. Another peptide containing alternating N-methyl amino acids but based on the sequence of a different fibril-forming protein, the human prion protein, is also not an inhibitor of Aβ40 fibrillogenesis. The nonmethylated version of the inhibitor peptide, NH2-KLVFFAE-CONH2 (Aβ16−22), is a weak fibrillogenesis inhibitor. Perhaps contrary to expectations, the Aβ16−22m peptide is highly soluble in aqueous media, and concentrations in excess of 40 mg/mL can be obtained in buffers of physiological pH and ionic strength, compared to only 2 mg/mL for Aβ16−22. Analytical ultracentrifugation demonstrates that Aβ16−22m is monomeric in buffer solution. Whereas Aβ16−22 is susceptible to cleavage by chymotrypsin, the methylated inhibitor peptide Aβ16−22m is completely resistant to this protease. Circular dichroic spectroscopy of Aβ16−22m indicates that this peptide is a β-strand, albeit with an unusual minimum at 226 nm. In summary, the inhibitor motif is that of alternating N-methyl and nonmethylated amino acids in a sequence critical for Aβ40 fibrillogenesis. 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In this paper we describe N-methyl amino acid containing congeners of the hydrophobic “core domain” of Aβ that inhibit the fibrillogenesis of full-length Aβ. These peptides also disassemble preformed fibrils of full-length Aβ. A key feature of the inhibitor peptides is that they contain N-methyl amino acids in alternating positions of the sequence. The most potent of these inhibitors, termed Aβ16−22m, has the sequence NH2-K(Me-L)V(Me-F)F(Me-A)E-CONH2. In contrast, a peptide, NH2-KL(Me-V)(Me-F)(Me-F)(Me-A)-E-CONH2, with N-methyl amino acids in consecutive order, is not a fibrillogenesis inhibitor. Another peptide containing alternating N-methyl amino acids but based on the sequence of a different fibril-forming protein, the human prion protein, is also not an inhibitor of Aβ40 fibrillogenesis. The nonmethylated version of the inhibitor peptide, NH2-KLVFFAE-CONH2 (Aβ16−22), is a weak fibrillogenesis inhibitor. Perhaps contrary to expectations, the Aβ16−22m peptide is highly soluble in aqueous media, and concentrations in excess of 40 mg/mL can be obtained in buffers of physiological pH and ionic strength, compared to only 2 mg/mL for Aβ16−22. Analytical ultracentrifugation demonstrates that Aβ16−22m is monomeric in buffer solution. Whereas Aβ16−22 is susceptible to cleavage by chymotrypsin, the methylated inhibitor peptide Aβ16−22m is completely resistant to this protease. Circular dichroic spectroscopy of Aβ16−22m indicates that this peptide is a β-strand, albeit with an unusual minimum at 226 nm. In summary, the inhibitor motif is that of alternating N-methyl and nonmethylated amino acids in a sequence critical for Aβ40 fibrillogenesis. These inhibitors appear to act by binding to growth sites of Aβ nuclei and/or fibrils and preventing the propagation of the network of hydrogen bonds that is essential for the formation of an extended β-sheet fibril.</description><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer Disease - pathology</subject><subject>Amino Acid Sequence</subject><subject>Amino Acids - metabolism</subject><subject>Amyloid beta-Peptides - antagonists & inhibitors</subject><subject>Amyloid beta-Peptides - chemical synthesis</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Amyloid beta-Peptides - ultrastructure</subject><subject>Chymotrypsin - metabolism</subject><subject>Drug Resistance</subject><subject>Humans</subject><subject>Methylation</subject><subject>Microscopy, Fluorescence</subject><subject>Molecular Sequence Data</subject><subject>Peptide Fragments - antagonists & inhibitors</subject><subject>Peptide Fragments - chemical synthesis</subject><subject>Peptide Fragments - metabolism</subject><subject>Peptide Fragments - ultrastructure</subject><subject>Protein Structure, Secondary</subject><subject>Protein Structure, Tertiary</subject><subject>Thiazoles - metabolism</subject><subject>Ultracentrifugation</subject><issn>0006-2960</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9u1DAQxi0EokvhwAsgX0D0EBg7jh0fo4VCpfKvLWfLSbxdF8dubS8ir8SRB-GZ8GpXhQOI08xofvN90nwIPSbwggAlL3sLQBnhX--gBWkoVEzK5i5aAACvqORwgB6kdFVGBoLdRweEMMYklwv0_cSvbW-zDR6HFf75o-qm2QU7PmdwhI9tH61z4dJ4k2zC2o_4lU06JTP1bv7nRcL9jM_XIeY_9ngZ_FYopm2XtfXWX-L31TuT17PD3WR9wN1gx-KTceeyiV5ng8-K9bgx6SG6t9IumUf7eog-H7--WL6tTj-8OVl2p5WuW8gV44I3K9JSEGSEpuY146Og5Q3MME4470lpmKRGD8AFUEHF0AvB2gZGAkN9iJ7tdK9juCm-WU02DcY57U3YJCVASmgb_l-QtETUkjYFPNqBQwwpRbNS19FOOs6KgNomqG4TLOyTveimn8z4m9xHVoBqB9iUzbfbvY5fFBe1aNTFx3P16YzXXBZ1KPzTHa-HpK7CpjzVpb8Y_wKdYrGI</recordid><startdate>20010717</startdate><enddate>20010717</enddate><creator>Gordon, David J</creator><creator>Sciarretta, Kimberly L</creator><creator>Meredith, Stephen C</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope></search><sort><creationdate>20010717</creationdate><title>Inhibition of β-Amyloid(40) Fibrillogenesis and Disassembly of β-Amyloid(40) Fibrils by Short β-Amyloid Congeners Containing N-Methyl Amino Acids at Alternate Residues</title><author>Gordon, David J ; Sciarretta, Kimberly L ; Meredith, Stephen C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a380t-46765f182071d0536346d722964e46166b14e4492eac06702727cb774850d10c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Alzheimer Disease - metabolism</topic><topic>Alzheimer Disease - pathology</topic><topic>Amino Acid Sequence</topic><topic>Amino Acids - metabolism</topic><topic>Amyloid beta-Peptides - antagonists & inhibitors</topic><topic>Amyloid beta-Peptides - chemical synthesis</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>Amyloid beta-Peptides - ultrastructure</topic><topic>Chymotrypsin - metabolism</topic><topic>Drug Resistance</topic><topic>Humans</topic><topic>Methylation</topic><topic>Microscopy, Fluorescence</topic><topic>Molecular Sequence Data</topic><topic>Peptide Fragments - antagonists & inhibitors</topic><topic>Peptide Fragments - chemical synthesis</topic><topic>Peptide Fragments - metabolism</topic><topic>Peptide Fragments - ultrastructure</topic><topic>Protein Structure, Secondary</topic><topic>Protein Structure, Tertiary</topic><topic>Thiazoles - metabolism</topic><topic>Ultracentrifugation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gordon, David J</creatorcontrib><creatorcontrib>Sciarretta, Kimberly L</creatorcontrib><creatorcontrib>Meredith, Stephen C</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Biochemistry (Easton)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gordon, David J</au><au>Sciarretta, Kimberly L</au><au>Meredith, Stephen C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of β-Amyloid(40) Fibrillogenesis and Disassembly of β-Amyloid(40) Fibrils by Short β-Amyloid Congeners Containing N-Methyl Amino Acids at Alternate Residues</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>2001-07-17</date><risdate>2001</risdate><volume>40</volume><issue>28</issue><spage>8237</spage><epage>8245</epage><pages>8237-8245</pages><issn>0006-2960</issn><eissn>1520-4995</eissn><abstract>A potential goal in the prevention or therapy of Alzheimer's disease is to decrease or eliminate neuritic plaques composed of fibrillar β-amyloid (Aβ). In this paper we describe N-methyl amino acid containing congeners of the hydrophobic “core domain” of Aβ that inhibit the fibrillogenesis of full-length Aβ. These peptides also disassemble preformed fibrils of full-length Aβ. A key feature of the inhibitor peptides is that they contain N-methyl amino acids in alternating positions of the sequence. The most potent of these inhibitors, termed Aβ16−22m, has the sequence NH2-K(Me-L)V(Me-F)F(Me-A)E-CONH2. In contrast, a peptide, NH2-KL(Me-V)(Me-F)(Me-F)(Me-A)-E-CONH2, with N-methyl amino acids in consecutive order, is not a fibrillogenesis inhibitor. Another peptide containing alternating N-methyl amino acids but based on the sequence of a different fibril-forming protein, the human prion protein, is also not an inhibitor of Aβ40 fibrillogenesis. The nonmethylated version of the inhibitor peptide, NH2-KLVFFAE-CONH2 (Aβ16−22), is a weak fibrillogenesis inhibitor. Perhaps contrary to expectations, the Aβ16−22m peptide is highly soluble in aqueous media, and concentrations in excess of 40 mg/mL can be obtained in buffers of physiological pH and ionic strength, compared to only 2 mg/mL for Aβ16−22. Analytical ultracentrifugation demonstrates that Aβ16−22m is monomeric in buffer solution. Whereas Aβ16−22 is susceptible to cleavage by chymotrypsin, the methylated inhibitor peptide Aβ16−22m is completely resistant to this protease. Circular dichroic spectroscopy of Aβ16−22m indicates that this peptide is a β-strand, albeit with an unusual minimum at 226 nm. In summary, the inhibitor motif is that of alternating N-methyl and nonmethylated amino acids in a sequence critical for Aβ40 fibrillogenesis. These inhibitors appear to act by binding to growth sites of Aβ nuclei and/or fibrils and preventing the propagation of the network of hydrogen bonds that is essential for the formation of an extended β-sheet fibril.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>11444969</pmid><doi>10.1021/bi002416v</doi><tpages>9</tpages></addata></record> |
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subjects | Alzheimer Disease - metabolism Alzheimer Disease - pathology Amino Acid Sequence Amino Acids - metabolism Amyloid beta-Peptides - antagonists & inhibitors Amyloid beta-Peptides - chemical synthesis Amyloid beta-Peptides - metabolism Amyloid beta-Peptides - ultrastructure Chymotrypsin - metabolism Drug Resistance Humans Methylation Microscopy, Fluorescence Molecular Sequence Data Peptide Fragments - antagonists & inhibitors Peptide Fragments - chemical synthesis Peptide Fragments - metabolism Peptide Fragments - ultrastructure Protein Structure, Secondary Protein Structure, Tertiary Thiazoles - metabolism Ultracentrifugation |
title | Inhibition of β-Amyloid(40) Fibrillogenesis and Disassembly of β-Amyloid(40) Fibrils by Short β-Amyloid Congeners Containing N-Methyl Amino Acids at Alternate Residues |
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