PMID- 37895969
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240210
IS  - 1424-8247 (Print)
IS  - 1424-8247 (Electronic)
IS  - 1424-8247 (Linking)
VI  - 16
IP  - 10
DP  - 2023 Oct 20
TI  - Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in 
      Diverse Neurodegeneration Models, and Extend C. elegans Life- and Healthspan.
LID - 10.3390/ph16101498 [doi]
LID - 1498
AB  - 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 C. elegans 
      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 C. elegans strain expressing human Abeta(1-42) 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 C. elegans lifespan by 15-30% (p < 0.001), placing them among 
      the most effective life-extension drugs. Because the lead drug in this family, 
      TDZD-8, inhibits GSK3beta, we used molecular-dynamic tools to assess whether these 
      analogs may also target GSK3beta. In silico modeling predicted that PNR886 or PNR962 
      would bind to the same allosteric pocket of inactive GSK3beta 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.
FAU - Kakraba, Samuel
AU  - Kakraba S
AUID- ORCID: 0000-0002-6362-5126
AD  - Department of Geriatrics, University of Arkansas for Medical Sciences, Little 
      Rock, AR 72205, USA.
FAU - Ayyadevara, Srinivas
AU  - Ayyadevara S
AD  - Department of Geriatrics, University of Arkansas for Medical Sciences, Little 
      Rock, AR 72205, USA.
AD  - Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA.
FAU - Mainali, Nirjal
AU  - Mainali N
AUID- ORCID: 0000-0001-9679-1174
AD  - Department of Geriatrics, University of Arkansas for Medical Sciences, Little 
      Rock, AR 72205, USA.
FAU - Balasubramaniam, Meenakshisundaram
AU  - Balasubramaniam M
AD  - Department of Geriatrics, University of Arkansas for Medical Sciences, Little 
      Rock, AR 72205, USA.
FAU - Bowroju, Suresh
AU  - Bowroju S
AUID- ORCID: 0000-0001-9906-0625
AD  - Department of Pharmaceutical Sciences, University of Arkansas for Medical 
      Sciences, Little Rock, AR 72205, USA.
FAU - Penthala, Narsimha Reddy
AU  - Penthala NR
AD  - Department of Pharmaceutical Sciences, University of Arkansas for Medical 
      Sciences, Little Rock, AR 72205, USA.
FAU - Atluri, Ramani
AU  - Atluri R
AD  - Department of Geriatrics, University of Arkansas for Medical Sciences, Little 
      Rock, AR 72205, USA.
FAU - Barger, Steven W
AU  - Barger SW
AD  - Department of Geriatrics, University of Arkansas for Medical Sciences, Little 
      Rock, AR 72205, USA.
AD  - Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA.
FAU - Griffin, Sue T
AU  - Griffin ST
AD  - Department of Geriatrics, University of Arkansas for Medical Sciences, Little 
      Rock, AR 72205, USA.
AD  - Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA.
FAU - Crooks, Peter A
AU  - Crooks PA
AD  - Department of Pharmaceutical Sciences, University of Arkansas for Medical 
      Sciences, Little Rock, AR 72205, USA.
FAU - Shmookler Reis, Robert J
AU  - Shmookler Reis RJ
AUID- ORCID: 0000-0002-4691-0734
AD  - Department of Geriatrics, University of Arkansas for Medical Sciences, Little 
      Rock, AR 72205, USA.
AD  - Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA.
LA  - eng
GR  - I01 BX001655/BX/BLRD VA/United States
GR  - P01 AG012411/AG/NIA NIH HHS/United States
GR  - R01 AG084473/AG/NIA NIH HHS/United States
GR  - IK6 BX004851/BX/BLRD VA/United States
PT  - Journal Article
DEP - 20231020
PL  - Switzerland
TA  - Pharmaceuticals (Basel)
JT  - Pharmaceuticals (Basel, Switzerland)
JID - 101238453
PMC - PMC10610358
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - aggregation
OT  - glycogen synthase kinase 3beta (GSK3beta)
OT  - molecular modeling
OT  - neurodegeneration
OT  - neurodegenerative disease
OT  - protein aggregation
OT  - proteostasis
OT  - thiadiazolidinones (TDZDs)
COIS- The authors declare no financial conflict of interest apart from intellectual 
      property rights for drugs described herein. RJSR, PAC, SA, SK, SB, NRP, and 
      others hold a patent on analogues PNR886 and PNR962. The University of Arkansas 
      for Medical Sciences (UAMS) and the U.S. Government (Dept. of Veteran Affairs) 
      jointly submitted patent claims on compounds PNR502, PNR886, and PNR962, inter 
      alia, for protection against Alzheimer's and other neurodegenerative diseases 
      (U.S. PCT filings 16/483366-2020, 63/163572A1-2021, 63/288998-2021, and 17/ 
      79638-2023). Potential royalty streams to RJSR, PAC, SA, SK, SB, and NRP may 
      occur consistent with the policies of these institutions. The funders had no role 
      in the design of the study; in the collection, analyses, or interpretation of 
      data; in the writing of the manuscript; or in the decision to publish the 
      results.
EDAT- 2023/10/28 11:48
MHDA- 2023/10/28 11:49
PMCR- 2023/10/20
CRDT- 2023/10/28 01:24
PHST- 2023/08/25 00:00 [received]
PHST- 2023/09/29 00:00 [revised]
PHST- 2023/10/02 00:00 [accepted]
PHST- 2023/10/28 11:49 [medline]
PHST- 2023/10/28 11:48 [pubmed]
PHST- 2023/10/28 01:24 [entrez]
PHST- 2023/10/20 00:00 [pmc-release]
AID - ph16101498 [pii]
AID - pharmaceuticals-16-01498 [pii]
AID - 10.3390/ph16101498 [doi]
PST - epublish
SO  - Pharmaceuticals (Basel). 2023 Oct 20;16(10):1498. doi: 10.3390/ph16101498.