Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer’s Disease and Related Disorders
<p dir="ltr">The field of Alzheimer’s disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues...
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2023
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| _version_ | 1864513507590930432 |
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| author | Jaunetta Hill (18255631) |
| author2 | Karim E. Shalaby (12267224) Syed W. Bihaqi (19457386) Bothaina H. Alansi (19457389) Benjamin Barlock (13119613) Keykavous Parang (281303) Richard Thompson (47003) Khalid Ouararhni (3145734) Nasser H. Zawia (18255646) |
| author2_role | author author author author author author author author |
| author_facet | Jaunetta Hill (18255631) Karim E. Shalaby (12267224) Syed W. Bihaqi (19457386) Bothaina H. Alansi (19457389) Benjamin Barlock (13119613) Keykavous Parang (281303) Richard Thompson (47003) Khalid Ouararhni (3145734) Nasser H. Zawia (18255646) |
| author_role | author |
| dc.creator.none.fl_str_mv | Jaunetta Hill (18255631) Karim E. Shalaby (12267224) Syed W. Bihaqi (19457386) Bothaina H. Alansi (19457389) Benjamin Barlock (13119613) Keykavous Parang (281303) Richard Thompson (47003) Khalid Ouararhni (3145734) Nasser H. Zawia (18255646) |
| dc.date.none.fl_str_mv | 2023-10-16T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.3390/ijms242015216 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Tolfenamic_Acid_Derivatives_A_New_Class_of_Transcriptional_Modulators_with_Potential_Therapeutic_Applications_for_Alzheimer_s_Disease_and_Related_Disorders/26796232 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Neurosciences Pharmacology and pharmaceutical sciences Alzheimer’s disease drug design drug development small molecules tolfenamic acid SP1 |
| dc.title.none.fl_str_mv | Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer’s Disease and Related Disorders |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">The field of Alzheimer’s disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they have serious side effects. Previously, we have shown in AD animal models that tolfenamic acid (TA) can lower the expression of AD-related genes and their products and subsequently reduce pathological burden and improve cognition. Using TA as a scaffold and the zinc finger domain of SP1 as a pharmacophore, we developed safer and more potent brain-penetrating analogs that interfere with sequence-specific DNA binding at transcription start sites and predominantly modulate the expression of SP1 target genes. More importantly, the proteome of treated cells displayed ~75% of the downregulated products as SP1 targets. Specific levels of SP1-driven genes and AD biomarkers such as amyloid precursor protein (APP) and Tau proteins were also decreased as part of this targeted systemic response. These small molecules, therefore, offer a viable alternative to achieving desired therapeutic outcomes by interfering with both amyloid and Tau pathways with limited off-target systemic changes.</p><h2>Other Information</h2><p dir="ltr">Published in: International Journal of Molecular Sciences<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/ijms242015216" target="_blank">https://dx.doi.org/10.3390/ijms242015216</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_8323a9a39ed9146efa297cf68b43728e |
| identifier_str_mv | 10.3390/ijms242015216 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26796232 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer’s Disease and Related DisordersJaunetta Hill (18255631)Karim E. Shalaby (12267224)Syed W. Bihaqi (19457386)Bothaina H. Alansi (19457389)Benjamin Barlock (13119613)Keykavous Parang (281303)Richard Thompson (47003)Khalid Ouararhni (3145734)Nasser H. Zawia (18255646)Biomedical and clinical sciencesClinical sciencesNeurosciencesPharmacology and pharmaceutical sciencesAlzheimer’s diseasedrug designdrug developmentsmall moleculestolfenamic acidSP1<p dir="ltr">The field of Alzheimer’s disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they have serious side effects. Previously, we have shown in AD animal models that tolfenamic acid (TA) can lower the expression of AD-related genes and their products and subsequently reduce pathological burden and improve cognition. Using TA as a scaffold and the zinc finger domain of SP1 as a pharmacophore, we developed safer and more potent brain-penetrating analogs that interfere with sequence-specific DNA binding at transcription start sites and predominantly modulate the expression of SP1 target genes. More importantly, the proteome of treated cells displayed ~75% of the downregulated products as SP1 targets. Specific levels of SP1-driven genes and AD biomarkers such as amyloid precursor protein (APP) and Tau proteins were also decreased as part of this targeted systemic response. These small molecules, therefore, offer a viable alternative to achieving desired therapeutic outcomes by interfering with both amyloid and Tau pathways with limited off-target systemic changes.</p><h2>Other Information</h2><p dir="ltr">Published in: International Journal of Molecular Sciences<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/ijms242015216" target="_blank">https://dx.doi.org/10.3390/ijms242015216</a></p>2023-10-16T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.3390/ijms242015216https://figshare.com/articles/journal_contribution/Tolfenamic_Acid_Derivatives_A_New_Class_of_Transcriptional_Modulators_with_Potential_Therapeutic_Applications_for_Alzheimer_s_Disease_and_Related_Disorders/26796232CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/267962322023-10-16T09:00:00Z |
| spellingShingle | Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer’s Disease and Related Disorders Jaunetta Hill (18255631) Biomedical and clinical sciences Clinical sciences Neurosciences Pharmacology and pharmaceutical sciences Alzheimer’s disease drug design drug development small molecules tolfenamic acid SP1 |
| status_str | publishedVersion |
| title | Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer’s Disease and Related Disorders |
| title_full | Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer’s Disease and Related Disorders |
| title_fullStr | Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer’s Disease and Related Disorders |
| title_full_unstemmed | Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer’s Disease and Related Disorders |
| title_short | Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer’s Disease and Related Disorders |
| title_sort | Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer’s Disease and Related Disorders |
| topic | Biomedical and clinical sciences Clinical sciences Neurosciences Pharmacology and pharmaceutical sciences Alzheimer’s disease drug design drug development small molecules tolfenamic acid SP1 |