ingest
cdrApp
2017-08-15T20:29:10.045Z
d91e81c8-5a8a-4e8a-976c-cad4e396e5ee
modifyDatastreamByValue
RELS-EXT
fedoraAdmin
2017-08-15T20:30:00.258Z
Setting exclusive relation
modifyDatastreamByValue
RELS-EXT
fedoraAdmin
2017-08-15T20:30:09.306Z
Setting exclusive relation
addDatastream
MD_TECHNICAL
fedoraAdmin
2017-08-15T20:30:18.365Z
Adding technical metadata derived by FITS
modifyDatastreamByValue
RELS-EXT
fedoraAdmin
2017-08-15T20:30:36.291Z
Setting exclusive relation
addDatastream
MD_FULL_TEXT
fedoraAdmin
2017-08-15T20:30:46.018Z
Adding full text metadata extracted by Apache Tika
modifyDatastreamByValue
RELS-EXT
fedoraAdmin
2017-08-15T20:31:04.407Z
Setting exclusive relation
modifyDatastreamByValue
RELS-EXT
cdrApp
2017-08-22T13:51:52.683Z
Setting exclusive relation
modifyDatastreamByValue
MD_DESCRIPTIVE
cdrApp
2017-08-29T13:47:44.641Z
modifyDatastreamByValue
MD_DESCRIPTIVE
cdrApp
2018-01-25T21:01:47.667Z
modifyDatastreamByValue
MD_DESCRIPTIVE
cdrApp
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modifyDatastreamByValue
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cdrApp
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modifyDatastreamByValue
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cdrApp
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modifyDatastreamByValue
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modifyDatastreamByValue
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cdrApp
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cdrApp
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modifyDatastreamByValue
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modifyDatastreamByValue
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cdrApp
2018-10-17T18:10:59.068Z
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cdrApp
2019-03-22T16:03:35.827Z
Kimberly
Barnash
Author
Pharmaceutical Sciences Program
Eshelman School of Pharmacy
A COMBINATORIAL PLATFORM FOR THE OPTIMIZATION OF PEPTIDOMIMETIC METHYL-LYSINE READER ANTAGONISTS
Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.
Spring 2017
2017
Pharmaceutical sciences
Organic chemistry
Biochemistry
chromodomain, combinatorial chemistry, histone, methyl-lysine, peptidomimetic, structure-based design
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Pharmaceutical Sciences
Stephen
Frye
Thesis advisor
Albert
Bowers
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Marcey
Waters
Thesis advisor
Michel
Gagne
Thesis advisor
text
Kimberly
Barnash
Author
Pharmaceutical Sciences Program
Eshelman School of Pharmacy
A Combinatorial Platform for The Optimization of Peptidomimetic Methyl-Lysine Reader Antagonists
Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.
Spring 2017
2017
Pharmaceutical sciences
Organic chemistry
Biochemistry
chromodomain, combinatorial chemistry, histone, methyl-lysine, peptidomimetic, structure-based design
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Pharmaceutical Sciences
Stephen
Frye
Thesis advisor
Albert
Bowers
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Marcey
Waters
Thesis advisor
Michel
Gagne
Thesis advisor
text
Kimberly
Barnash
Creator
Pharmaceutical Sciences Program
Eshelman School of Pharmacy
A Combinatorial Platform for The Optimization of Peptidomimetic Methyl-Lysine
Reader Antagonists
Post-translational modification of histone N-terminal tails mediates
chromatin compaction and, consequently, DNA replication, transcription, and repair. While
numerous post-translational modifications decorate histone tails, lysine methylation is an
abundant mark important for both gene activation and repression. Methyl-lysine (Kme)
readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of
Kme readers faces numerous challenges due to the broad surface-groove interactions between
readers and their cognate histone peptides; yet, the increasing interest in understanding
chromatin-modifying complexes suggests tractable lead compounds for Kme readers are
critical for elucidating the mechanisms of chromatin dysregulation in disease states and
validating the druggability of these domains and complexes. The successful discovery of a
peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1)
chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition
of reader function. Unfortunately, the systematic modification of
peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit
discovery against Kme readers. Through the exploration of biased chemical space via
combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme
reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit
discovery strategy with subsequent optimization via iterative targeted libraries.
Peptide-to-peptidomimetic optimization through targeted library design was applied based
on structure-guided library design around the interaction of the endogenous peptide ligand
with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery
of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for
off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand,
and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the
generalizability of a peptidomimetic combinatorial platform for the optimization of Kme
reader ligands in a target class manner.
Spring 2017
2017
Pharmaceutical sciences
Organic chemistry
Biochemistry
chromodomain, combinatorial chemistry, histone,
methyl-lysine, peptidomimetic, structure-based design
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting
institution
Pharmaceutical Sciences
Stephen
Frye
Thesis advisor
Albert
Bowers
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Marcey
Waters
Thesis advisor
Michel
Gagne
Thesis advisor
text
Kimberly
Barnash
Creator
Pharmaceutical Sciences Program
Eshelman School of Pharmacy
A Combinatorial Platform for The Optimization of Peptidomimetic Methyl-Lysine Reader Antagonists
Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.
Spring 2017
2017
Pharmaceutical sciences
Organic chemistry
Biochemistry
chromodomain, combinatorial chemistry, histone, methyl-lysine, peptidomimetic, structure-based design
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Pharmaceutical Sciences
Stephen
Frye
Thesis advisor
Albert
Bowers
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Marcey
Waters
Thesis advisor
Michel
Gagne
Thesis advisor
text
Kimberly
Barnash
Creator
Division of Chemical Biology and Medicinal Chemistry
Eshelman School of Pharmacy
A Combinatorial Platform for The Optimization of Peptidomimetic Methyl-Lysine Reader Antagonists
Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.
Spring 2017
2017
Pharmaceutical sciences
Organic chemistry
Biochemistry
chromodomain, combinatorial chemistry, histone, methyl-lysine, peptidomimetic, structure-based design
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Pharmaceutical Sciences
Stephen
Frye
Thesis advisor
Albert
Bowers
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Marcey
Waters
Thesis advisor
Michel
Gagne
Thesis advisor
text
Kimberly
Barnash
Creator
Division of Chemical Biology and Medicinal Chemistry
Eshelman School of Pharmacy
A Combinatorial Platform for The Optimization of Peptidomimetic Methyl-Lysine Reader Antagonists
Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.
2017-05
2017
Pharmaceutical sciences
Organic chemistry
Biochemistry
chromodomain, combinatorial chemistry, histone, methyl-lysine, peptidomimetic, structure-based design
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Pharmaceutical Sciences
Stephen
Frye
Thesis advisor
Albert
Bowers
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Marcey
Waters
Thesis advisor
Michel
Gagne
Thesis advisor
text
Kimberly
Barnash
Creator
Division of Chemical Biology and Medicinal Chemistry
Eshelman School of Pharmacy
A Combinatorial Platform for The Optimization of Peptidomimetic Methyl-Lysine Reader Antagonists
Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.
2017
Pharmaceutical sciences
Organic chemistry
Biochemistry
chromodomain, combinatorial chemistry, histone, methyl-lysine, peptidomimetic, structure-based design
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Pharmaceutical Sciences
Stephen
Frye
Thesis advisor
Albert
Bowers
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Marcey
Waters
Thesis advisor
Michel
Gagne
Thesis advisor
text
2017-05
Kimberly
Barnash
Creator
Division of Chemical Biology and Medicinal Chemistry
Eshelman School of Pharmacy
A Combinatorial Platform for The Optimization of Peptidomimetic Methyl-Lysine Reader Antagonists
Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.
2017
Pharmaceutical sciences
Organic chemistry
Biochemistry
chromodomain, combinatorial chemistry, histone, methyl-lysine, peptidomimetic, structure-based design
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Pharmaceutical Sciences
Stephen
Frye
Thesis advisor
Albert
Bowers
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Marcey
Waters
Thesis advisor
Michel
Gagne
Thesis advisor
text
2017-05
Kimberly
Barnash
Creator
Division of Chemical Biology and Medicinal Chemistry
Eshelman School of Pharmacy
A Combinatorial Platform for The Optimization of Peptidomimetic Methyl-Lysine Reader Antagonists
Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.
2017
Pharmaceutical sciences
Organic chemistry
Biochemistry
chromodomain, combinatorial chemistry, histone, methyl-lysine, peptidomimetic, structure-based design
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Pharmaceutical Sciences
Stephen
Frye
Thesis advisor
Albert
Bowers
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Marcey
Waters
Thesis advisor
Michel
Gagne
Thesis advisor
text
2017-05
Kimberly
Barnash
Creator
Division of Chemical Biology and Medicinal Chemistry
Eshelman School of Pharmacy
A Combinatorial Platform for The Optimization of Peptidomimetic Methyl-Lysine Reader Antagonists
Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.
2017
Pharmaceutical sciences
Organic chemistry
Biochemistry
chromodomain, combinatorial chemistry, histone, methyl-lysine, peptidomimetic, structure-based design
eng
Doctor of Philosophy
Dissertation
Pharmaceutical Sciences
Stephen
Frye
Thesis advisor
Albert
Bowers
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Marcey
Waters
Thesis advisor
Michel
Gagne
Thesis advisor
text
2017-05
University of North Carolina at Chapel Hill
Degree granting institution
Kimberly
Barnash
Creator
Division of Chemical Biology and Medicinal Chemistry
Eshelman School of Pharmacy
A Combinatorial Platform for The Optimization of Peptidomimetic Methyl-Lysine Reader Antagonists
Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.
2017
Pharmaceutical sciences
Organic chemistry
Biochemistry
chromodomain; combinatorial chemistry; histone; methyl-lysine; peptidomimetic; structure-based design
eng
Doctor of Philosophy
Dissertation
Pharmaceutical Sciences
Stephen
Frye
Thesis advisor
Albert
Bowers
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Marcey
Waters
Thesis advisor
Michel
Gagne
Thesis advisor
text
2017-05
University of North Carolina at Chapel Hill
Degree granting institution
Kimberly
Barnash
Creator
Division of Chemical Biology and Medicinal Chemistry
Eshelman School of Pharmacy
A Combinatorial Platform for The Optimization of Peptidomimetic Methyl-Lysine Reader Antagonists
Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.
2017
Pharmaceutical sciences
Organic chemistry
Biochemistry
chromodomain, combinatorial chemistry, histone, methyl-lysine, peptidomimetic, structure-based design
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Pharmaceutical Sciences
Stephen
Frye
Thesis advisor
Albert
Bowers
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Marcey
Waters
Thesis advisor
Michel
Gagne
Thesis advisor
text
2017-05
Kimberly
Barnash
Creator
Division of Chemical Biology and Medicinal Chemistry
Eshelman School of Pharmacy
A Combinatorial Platform for The Optimization of Peptidomimetic Methyl-Lysine Reader Antagonists
Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.
2017
Pharmaceutical sciences
Organic chemistry
Biochemistry
chromodomain, combinatorial chemistry, histone, methyl-lysine, peptidomimetic, structure-based design
eng
Doctor of Philosophy
Dissertation
Pharmaceutical Sciences
Stephen
Frye
Thesis advisor
Albert
Bowers
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Marcey
Waters
Thesis advisor
Michel
Gagne
Thesis advisor
text
2017-05
University of North Carolina at Chapel Hill
Degree granting institution
Kimberly
Barnash
Creator
Division of Chemical Biology and Medicinal Chemistry
Eshelman School of Pharmacy
A Combinatorial Platform for The Optimization of Peptidomimetic Methyl-Lysine Reader Antagonists
Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.
2017
Pharmaceutical sciences
Organic chemistry
Biochemistry
chromodomain; combinatorial chemistry; histone; methyl-lysine; peptidomimetic; structure-based design
eng
Doctor of Philosophy
Dissertation
Stephen
Frye
Thesis advisor
Albert
Bowers
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Marcey
Waters
Thesis advisor
Michel
Gagne
Thesis advisor
text
2017-05
University of North Carolina at Chapel Hill
Degree granting institution
Barnash_unc_0153D_17141.pdf
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2019-08-15T00:00:00
2017-06-03T19:33:42Z
proquest
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12867920
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