PMID- 38055197
OWN - NLM
STAT- MEDLINE
DCOM- 20240205
LR  - 20240406
IS  - 1439-7633 (Electronic)
IS  - 1439-4227 (Print)
IS  - 1439-4227 (Linking)
VI  - 25
IP  - 3
DP  - 2024 Feb 1
TI  - Discovery and Development of Cyclic Peptide Proteasome Stimulators.
PG  - e202300671
LID - 10.1002/cbic.202300671 [doi]
AB  - The proteasome degrades proteins, which is essential for cellular homeostasis. 
      Ubiquitin independent proteolysis degrades highly disordered and misfolded 
      proteins. A decline of proteasomal activity has been associated with multiple 
      neurodegenerative diseases due to the accumulation of misfolded proteins. In this 
      work, cyclic peptide proteasome stimulators (CyPPSs) that enhance the clearance 
      of misfolded proteins were discovered. In the initial screen of predicted natural 
      products (pNPs), several cyclic peptides were found to stimulate the 20S core 
      particle (20S CP). Development of a robust structural activity relationship led 
      to the identification of potent, cell permeable CyPPSs. In vitro assays revealed 
      that CyPPSs stimulate degradation of highly disordered and misfolded proteins 
      without affecting ordered proteins. Furthermore, using a novel flow-based assay 
      for proteasome activity, several CyPPSs were found to stimulate the 20S CP in 
      cellulo. Overall, this work describes the development of CyPPSs as chemical tools 
      capable of stimulating the proteasome and provides strong support for proteasome 
      stimulation as a therapeutic strategy for neurodegenerative diseases.
CI  - (c) 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.
FAU - Nelson, Samantha
AU  - Nelson S
AUID- ORCID: 0000-0003-2850-7105
AD  - Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 
      West Lafayette, Indiana, 47906, USA.
FAU - Harris, Timothy J
AU  - Harris TJ
AD  - Department of Pharmaceutical Sciences, University of California-Irvine, Irvine, 
      California, 92697, USA.
FAU - Muli, Christine S
AU  - Muli CS
AD  - Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 
      West Lafayette, Indiana, 47906, USA.
FAU - Maresh, Marianne E
AU  - Maresh ME
AD  - Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 
      West Lafayette, Indiana, 47906, USA.
FAU - Baker, Braden
AU  - Baker B
AD  - Department of Chemistry, Purdue University, West Lafayette, Indiana, 47906, USA.
FAU - Smith, Chloe
AU  - Smith C
AD  - Department of Chemistry, Purdue University, West Lafayette, Indiana, 47906, USA.
FAU - Neumann, Chris
AU  - Neumann C
AD  - Department of Chemistry, Purdue University, West Lafayette, Indiana, 47906, USA.
FAU - Trader, Darci J
AU  - Trader DJ
AD  - Department of Pharmaceutical Sciences, University of California-Irvine, Irvine, 
      California, 92697, USA.
FAU - Parkinson, Elizabeth I
AU  - Parkinson EI
AUID- ORCID: 0000-0002-3665-5522
AD  - Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 
      West Lafayette, Indiana, 47906, USA.
AD  - Department of Chemistry, Purdue University, West Lafayette, Indiana, 47906, USA.
LA  - eng
GR  - F31 CA247327/CA/NCI NIH HHS/United States
GR  - R35 GM138002/GM/NIGMS NIH HHS/United States
GR  - F31CA247327/NH/NIH HHS/United States
GR  - 1R35GM138002-01/NH/NIH HHS/United States
GR  - R01AI150847/NH/NIH HHS/United States
GR  - P30 CA023168/CA/NCI NIH HHS/United States
GR  - R01 AI150847/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20231215
PL  - Germany
TA  - Chembiochem
JT  - Chembiochem : a European journal of chemical biology
JID - 100937360
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - 0 (Peptides, Cyclic)
RN  - 0 (Proteins)
SB  - IM
MH  - Humans
MH  - *Proteasome Endopeptidase Complex/metabolism
MH  - Peptides, Cyclic/pharmacology/metabolism
MH  - Proteolysis
MH  - Proteins/metabolism
MH  - *Neurodegenerative Diseases/drug therapy
PMC - PMC10993313
MID - NIHMS1980030
OTO - NOTNLM
OT  - macrocycles
OT  - peptides
OT  - proteasome
OT  - stimulation
COIS- Conflicts of interest. The authors declare the following financial 
      interests/personal relationships which may be considered as potential competing 
      interests: Prof. Trader is a shareholder and consultant for Booster Therapeutics, 
      GmbH. Other author declares no conflict of interest.
EDAT- 2023/12/06 12:42
MHDA- 2024/02/05 06:43
PMCR- 2024/04/04
CRDT- 2023/12/06 11:14
PHST- 2023/12/01 00:00 [revised]
PHST- 2023/09/29 00:00 [received]
PHST- 2024/02/05 06:43 [medline]
PHST- 2023/12/06 12:42 [pubmed]
PHST- 2023/12/06 11:14 [entrez]
PHST- 2024/04/04 00:00 [pmc-release]
AID - 10.1002/cbic.202300671 [doi]
PST - ppublish
SO  - Chembiochem. 2024 Feb 1;25(3):e202300671. doi: 10.1002/cbic.202300671. Epub 2023 
      Dec 15.