Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend <i>C. elegans</i> Life- and Healthspan
Chronic, low-grade inflammation has been implicated in aging and age-dependent conditions, including Alzheimer’s disease, cardiomyopathy, and cancer. One of the age-associated processes underlying chronic inflammation is protein aggregation, which is implicated in neuroinflammation and a broad spect...
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MDPI AG
2023-10-01
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| Online Access: | https://www.mdpi.com/1424-8247/16/10/1498 |
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| author | Samuel Kakraba Srinivas Ayyadevara Nirjal Mainali Meenakshisundaram Balasubramaniam Suresh Bowroju Narsimha Reddy Penthala Ramani Atluri Steven W. Barger Sue T. Griffin Peter A. Crooks Robert J. Shmookler Reis |
| author_facet | Samuel Kakraba Srinivas Ayyadevara Nirjal Mainali Meenakshisundaram Balasubramaniam Suresh Bowroju Narsimha Reddy Penthala Ramani Atluri Steven W. Barger Sue T. Griffin Peter A. Crooks Robert J. Shmookler Reis |
| author_sort | Samuel Kakraba |
| collection | DOAJ |
| description | Chronic, low-grade inflammation has been implicated in aging and age-dependent conditions, including Alzheimer’s disease, cardiomyopathy, and cancer. One of the age-associated processes underlying chronic inflammation is protein aggregation, which is implicated in neuroinflammation and a broad spectrum of neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s diseases. We screened a panel of bioactive thiadiazolidinones (TDZDs) from our in-house library for rescue of protein aggregation in human-cell and <i>C. elegans</i> models of neurodegeneration. Among the tested TDZD analogs, PNR886 and PNR962 were most effective, significantly reducing both the number and intensity of Alzheimer-like tau and amyloid aggregates in human cell-culture models of pathogenic aggregation. A <i>C. elegans</i> strain expressing human Aβ<sub>1–42</sub> in muscle, leading to AD-like amyloidopathy, developed fewer and smaller aggregates after PNR886 or PNR962 treatment. Moreover, age-progressive paralysis was reduced 90% by PNR886 and 75% by PNR962, and “healthspan” (the median duration of spontaneous motility) was extended 29% and 62%, respectively. These TDZD analogs also extended wild-type <i>C. elegans</i> lifespan by 15–30% (<i>p</i> < 0.001), placing them among the most effective life-extension drugs. Because the lead drug in this family, TDZD-8, inhibits GSK3β, we used molecular-dynamic tools to assess whether these analogs may also target GSK3β. In silico modeling predicted that PNR886 or PNR962 would bind to the same allosteric pocket of inactive GSK3β as TDZD-8, employing the same pharmacophore but attaching with greater avidity. PNR886 and PNR962 are thus compelling candidate drugs for treatment of tau- and amyloid-associated neurodegenerative diseases such as AD, potentially also reducing all-cause mortality. |
| first_indexed | 2024-03-10T20:58:40Z |
| format | Article |
| id | doaj.art-5ef6117e54514590994189c991ada0a2 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T20:58:40Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-5ef6117e54514590994189c991ada0a22023-11-19T17:43:22ZengMDPI AGPharmaceuticals1424-82472023-10-011610149810.3390/ph16101498Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend <i>C. elegans</i> Life- and HealthspanSamuel Kakraba0Srinivas Ayyadevara1Nirjal Mainali2Meenakshisundaram Balasubramaniam3Suresh Bowroju4Narsimha Reddy Penthala5Ramani Atluri6Steven W. Barger7Sue T. Griffin8Peter A. Crooks9Robert J. Shmookler Reis10Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADepartment of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADepartment of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADepartment of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADepartment of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADepartment of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADepartment of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADepartment of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADepartment of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADepartment of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADepartment of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USAChronic, low-grade inflammation has been implicated in aging and age-dependent conditions, including Alzheimer’s disease, cardiomyopathy, and cancer. One of the age-associated processes underlying chronic inflammation is protein aggregation, which is implicated in neuroinflammation and a broad spectrum of neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s diseases. We screened a panel of bioactive thiadiazolidinones (TDZDs) from our in-house library for rescue of protein aggregation in human-cell and <i>C. elegans</i> models of neurodegeneration. Among the tested TDZD analogs, PNR886 and PNR962 were most effective, significantly reducing both the number and intensity of Alzheimer-like tau and amyloid aggregates in human cell-culture models of pathogenic aggregation. A <i>C. elegans</i> strain expressing human Aβ<sub>1–42</sub> in muscle, leading to AD-like amyloidopathy, developed fewer and smaller aggregates after PNR886 or PNR962 treatment. Moreover, age-progressive paralysis was reduced 90% by PNR886 and 75% by PNR962, and “healthspan” (the median duration of spontaneous motility) was extended 29% and 62%, respectively. These TDZD analogs also extended wild-type <i>C. elegans</i> lifespan by 15–30% (<i>p</i> < 0.001), placing them among the most effective life-extension drugs. Because the lead drug in this family, TDZD-8, inhibits GSK3β, we used molecular-dynamic tools to assess whether these analogs may also target GSK3β. In silico modeling predicted that PNR886 or PNR962 would bind to the same allosteric pocket of inactive GSK3β as TDZD-8, employing the same pharmacophore but attaching with greater avidity. PNR886 and PNR962 are thus compelling candidate drugs for treatment of tau- and amyloid-associated neurodegenerative diseases such as AD, potentially also reducing all-cause mortality.https://www.mdpi.com/1424-8247/16/10/1498aggregationAlzheimer’s diseaseglycogen synthase kinase 3β (GSK3β)molecular modelingneurodegenerationneurodegenerative disease |
| spellingShingle | Samuel Kakraba Srinivas Ayyadevara Nirjal Mainali Meenakshisundaram Balasubramaniam Suresh Bowroju Narsimha Reddy Penthala Ramani Atluri Steven W. Barger Sue T. Griffin Peter A. Crooks Robert J. Shmookler Reis Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend <i>C. elegans</i> Life- and Healthspan Pharmaceuticals aggregation Alzheimer’s disease glycogen synthase kinase 3β (GSK3β) molecular modeling neurodegeneration neurodegenerative disease |
| title | Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend <i>C. elegans</i> Life- and Healthspan |
| title_full | Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend <i>C. elegans</i> Life- and Healthspan |
| title_fullStr | Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend <i>C. elegans</i> Life- and Healthspan |
| title_full_unstemmed | Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend <i>C. elegans</i> Life- and Healthspan |
| title_short | Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend <i>C. elegans</i> Life- and Healthspan |
| title_sort | thiadiazolidinone tdzd analogs inhibit aggregation mediated pathology in diverse neurodegeneration models and extend i c elegans i life and healthspan |
| topic | aggregation Alzheimer’s disease glycogen synthase kinase 3β (GSK3β) molecular modeling neurodegeneration neurodegenerative disease |
| url | https://www.mdpi.com/1424-8247/16/10/1498 |
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