A Small Molecule Stabilizes the Disordered Native State of the Alzheimer’s Aβ Peptide
The stabilization of native states of proteins is a powerful drug discovery strategy. It is still unclear, however, whether this approach can be applied to intrinsically disordered proteins. Here, we report a small molecule that stabilizes the native state of the Aβ42 peptide, an intrinsically disor...
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| Veröffentlicht in: | ACS chemical neuroscience 2022-06, Vol.13 (12), p.1738-1745 |
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| container_title | ACS chemical neuroscience |
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| creator | Löhr, Thomas Kohlhoff, Kai Heller, Gabriella T. Camilloni, Carlo Vendruscolo, Michele |
| description | The stabilization of native states of proteins is a powerful drug discovery strategy. It is still unclear, however, whether this approach can be applied to intrinsically disordered proteins. Here, we report a small molecule that stabilizes the native state of the Aβ42 peptide, an intrinsically disordered protein fragment associated with Alzheimer’s disease. We show that this stabilization takes place by a disordered binding mechanism, in which both the small molecule and the Aβ42 peptide remain disordered. This disordered binding mechanism involves enthalpically favorable local π-stacking interactions coupled with entropically advantageous global effects. These results indicate that small molecules can stabilize disordered proteins in their native states through transient non-specific interactions that provide enthalpic gain while simultaneously increasing the conformational entropy of the proteins. |
| doi_str_mv | 10.1021/acschemneuro.2c00116 |
| format | Article |
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Neurosci</addtitle><description>The stabilization of native states of proteins is a powerful drug discovery strategy. It is still unclear, however, whether this approach can be applied to intrinsically disordered proteins. Here, we report a small molecule that stabilizes the native state of the Aβ42 peptide, an intrinsically disordered protein fragment associated with Alzheimer’s disease. We show that this stabilization takes place by a disordered binding mechanism, in which both the small molecule and the Aβ42 peptide remain disordered. This disordered binding mechanism involves enthalpically favorable local π-stacking interactions coupled with entropically advantageous global effects. These results indicate that small molecules can stabilize disordered proteins in their native states through transient non-specific interactions that provide enthalpic gain while simultaneously increasing the conformational entropy of the proteins.</description><subject>Alzheimer Disease - drug therapy</subject><subject>Alzheimer Disease - metabolism</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Entropy</subject><subject>Humans</subject><subject>Intrinsically Disordered Proteins - metabolism</subject><subject>Peptide Fragments - metabolism</subject><issn>1948-7193</issn><issn>1948-7193</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kctKxDAYhYMo3t9AJEs3o0naps1GGLyDN1DBXUjTP04kbcakFXTla_gaPogP4ZNYnVHGjauEnO-c_ycHoQ1KtilhdEfpqEdQN9AFv800IZTyObRMRVoMciqS-Zn7ElqJ8Z4QLkjBF9FSkvFUMF4so9shvqqVc_jMO9CdA3zVqtI6-wwRtyPA-zb6UEGACp-r1j5-Ay1gb77loXsega0hfLy8Rjx8f8OXMG5tBWtowSgXYX16rqKbw4PrvePB6cXRyd7wdKDSVLSDsuLCEGIMUKqZIZrmZUarIlHcMJ0VKVeFYQZYWVU6ZyKlZc4h4f2TyUCbZBXtTnLHXVlDpaFpg3JyHGytwpP0ysq_SmNH8s4_SsFImnPWB2xNA4J_6CC2srZRg3OqAd9FyXjOcpIUIuvRdILq4GMMYH7HUCK_SpGzpchpKb1tc3bFX9NPCz1AJkBvl_e-C03_Y_9nfgJvoaBo</recordid><startdate>20220615</startdate><enddate>20220615</enddate><creator>Löhr, Thomas</creator><creator>Kohlhoff, Kai</creator><creator>Heller, Gabriella T.</creator><creator>Camilloni, Carlo</creator><creator>Vendruscolo, Michele</creator><general>American Chemical Society</general><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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9923-8590</orcidid><orcidid>https://orcid.org/0000-0002-3616-1610</orcidid></search><sort><creationdate>20220615</creationdate><title>A Small Molecule Stabilizes the Disordered Native State of the Alzheimer’s Aβ Peptide</title><author>Löhr, Thomas ; Kohlhoff, Kai ; Heller, Gabriella T. ; Camilloni, Carlo ; Vendruscolo, Michele</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a449t-bd69f00ffe11c2f0c17b51d83a6f2c5846a8f2fe2bddc72941b76e362fef5ecf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Alzheimer Disease - drug therapy</topic><topic>Alzheimer Disease - metabolism</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>Entropy</topic><topic>Humans</topic><topic>Intrinsically Disordered Proteins - metabolism</topic><topic>Peptide Fragments - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Löhr, Thomas</creatorcontrib><creatorcontrib>Kohlhoff, Kai</creatorcontrib><creatorcontrib>Heller, Gabriella T.</creatorcontrib><creatorcontrib>Camilloni, Carlo</creatorcontrib><creatorcontrib>Vendruscolo, Michele</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>ACS chemical neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Löhr, Thomas</au><au>Kohlhoff, Kai</au><au>Heller, Gabriella T.</au><au>Camilloni, Carlo</au><au>Vendruscolo, Michele</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Small Molecule Stabilizes the Disordered Native State of the Alzheimer’s Aβ Peptide</atitle><jtitle>ACS chemical neuroscience</jtitle><addtitle>ACS Chem. Neurosci</addtitle><date>2022-06-15</date><risdate>2022</risdate><volume>13</volume><issue>12</issue><spage>1738</spage><epage>1745</epage><pages>1738-1745</pages><issn>1948-7193</issn><eissn>1948-7193</eissn><abstract>The stabilization of native states of proteins is a powerful drug discovery strategy. It is still unclear, however, whether this approach can be applied to intrinsically disordered proteins. Here, we report a small molecule that stabilizes the native state of the Aβ42 peptide, an intrinsically disordered protein fragment associated with Alzheimer’s disease. We show that this stabilization takes place by a disordered binding mechanism, in which both the small molecule and the Aβ42 peptide remain disordered. This disordered binding mechanism involves enthalpically favorable local π-stacking interactions coupled with entropically advantageous global effects. 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| fulltext | fulltext |
| identifier | ISSN: 1948-7193 |
| ispartof | ACS chemical neuroscience, 2022-06, Vol.13 (12), p.1738-1745 |
| issn | 1948-7193 1948-7193 |
| language | eng |
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| source | ACS Publications; MEDLINE |
| subjects | Alzheimer Disease - drug therapy Alzheimer Disease - metabolism Amyloid beta-Peptides - metabolism Entropy Humans Intrinsically Disordered Proteins - metabolism Peptide Fragments - metabolism |
| title | A Small Molecule Stabilizes the Disordered Native State of the Alzheimer’s Aβ Peptide |
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