Peter J. Cossar
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View article: Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity
Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity Open
The Carbohydrate Response Element Binding Protein (ChREBP) is a glucose-responsive transcription factor (TF) with two major splice isoforms (α and β). In chronic hyperglycemia and glucolipotoxicity, ChREBPα-mediated ChREBPβ expression surg…
View article: Modulation of Protein–Protein Interactions with Molecular Glues in a Synthetic Condensate Platform
Modulation of Protein–Protein Interactions with Molecular Glues in a Synthetic Condensate Platform Open
Misregulation of protein-protein interactions (PPIs) underlies many diseases; hence, molecules that stabilize PPIs, known as molecular glues, are promising drug candidates. Identification of novel molecular glues is highly challenging amon…
View article: Site-specific molecular glues for the 14-3-3/Tau pS214 protein–protein interaction <i>via</i> reversible covalent imine tethering
Site-specific molecular glues for the 14-3-3/Tau pS214 protein–protein interaction <i>via</i> reversible covalent imine tethering Open
The unique molecular topologies of the two different binding sites of the Tau/14-3-3 protein–protein interaction were exploited to develop selective dynamic covalent molecular glues for the Tau pS214 site.
View article: Proximity-enhanced cysteine–histidine crosslinking for elucidating intrinsically disordered and other protein complexes
Proximity-enhanced cysteine–histidine crosslinking for elucidating intrinsically disordered and other protein complexes Open
A novel proximity-enhanced crosslinker using histidine–cysteine trapping uncovers a cryptic 14-3-3/hyperphosphorylated Tau interaction via Ser356, advancing the understanding of IDP interactions and prompting a re-evaluation of 14-3-3/Tau …
View article: 14‐3‐3 Protein‐Protein Interactions: From Mechanistic Understanding to Their Small‐Molecule Stabilization
14‐3‐3 Protein‐Protein Interactions: From Mechanistic Understanding to Their Small‐Molecule Stabilization Open
Protein‐protein interactions (PPIs) are of utmost importance for maintenance of cellular homeostasis. Herein, a central role can be found for 14‐3‐3 proteins. These hub‐proteins are known to bind hundreds of interaction partners, thereby r…
View article: Estrogen Receptor α/14-3-3 molecular glues as alternative treatment strategy for endocrine resistant breast cancer
Estrogen Receptor α/14-3-3 molecular glues as alternative treatment strategy for endocrine resistant breast cancer Open
Summary Endocrine resistance in breast cancer treatment is a major clinical hurdle, causing an urgent need for alternative treatment modalities. The suppressive protein-protein interaction (PPI) between Estrogen Receptor alpha (ERα) and th…
View article: Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity
Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity Open
The Carbohydrate Response Element Binding Protein (ChREBP) is a glucose-responsive transcription factor (TF) with two major splice isoforms (α and β). In chronic hyperglycemia and glucolipotoxicity, ChREBPα-mediated ChREBPβ expression surg…
View article: Discovery of 14‐3‐3 PPI Stabilizers by Extension of an Amidine‐Substituted Thiophene Fragment
Discovery of 14‐3‐3 PPI Stabilizers by Extension of an Amidine‐Substituted Thiophene Fragment Open
Protein‐protein interaction (PPI) modulation is a promising approach in drug discovery with the potential to expand the ‘druggable’ proteome and develop new therapeutic strategies. While there have been significant advancements in methodol…
View article: A simple method for developing lysine targeted covalent protein reagents
A simple method for developing lysine targeted covalent protein reagents Open
There is a growing demand for covalent tool compounds and chemical probes to investigate and perturb protein function and dysregulation. The combination of a covalent electrophile with a peptide or protein-based scaffold with an extended b…
View article: Reversible Dual-Covalent Molecular Locking of the 14-3-3/ERRγ Protein–Protein Interaction as a Molecular Glue Drug Discovery Approach
Reversible Dual-Covalent Molecular Locking of the 14-3-3/ERRγ Protein–Protein Interaction as a Molecular Glue Drug Discovery Approach Open
Molecules that stabilize protein-protein interactions (PPIs) are invaluable as tool compounds for biophysics and (structural) biology, and as starting points for molecular glue drug discovery. However, identifying initial starting points f…
View article: Novel piperazine-1,2,3-triazole leads for the potential treatment of pancreatic cancer
Novel piperazine-1,2,3-triazole leads for the potential treatment of pancreatic cancer Open
Tight binding in the S100A2–p53 interaction groove = sub micromolar potencies against pancreatic cancer cell lines.
View article: Tracking the mechanism of covalent molecular glue stabilization using native mass spectrometry
Tracking the mechanism of covalent molecular glue stabilization using native mass spectrometry Open
The molecular mechanisms underlying molecular glue protein complex stabilization are poorly understood. In this study, we kinetically investigate covalent molecular glue stabilization of a canonical protein–protein interaction using native…
View article: Amino Alcohols as Potential Antibiotic and Antifungal Leads
Amino Alcohols as Potential Antibiotic and Antifungal Leads Open
Five focused compound libraries (forty-nine compounds), based on prior studies in our laboratory were synthesized and screened for antibiotic and anti-fungal activity against S. aureus, E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, …
View article: Early identification of cooperative fragments for protein-protein interaction stabilization
Early identification of cooperative fragments for protein-protein interaction stabilization Open
Modulating protein-protein interactions (PPIs) is an effective approach to drug discovery, with several drugs in the clinic that inhibit PPIs. The orthogonal approach of PPI stabilization has developed slowly, a function of the complicated…
View article: Functional mapping of the 14-3-3 hub protein as a guide to design 14-3-3 molecular glues
Functional mapping of the 14-3-3 hub protein as a guide to design 14-3-3 molecular glues Open
The functional mapping of a 14-3-3 protein complex, by means of peptide truncations and point mutations, as an approach to identify critical hotspots regions for 14-3-3 molecular glue drug design.
View article: An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-κB—Utilizing a Reversible Covalent Tethering Approach
An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-κB—Utilizing a Reversible Covalent Tethering Approach Open
Protein-protein modulation has emerged as a proven approach to drug discovery. While significant progress has been gained in developing protein-protein interaction (PPI) inhibitors, the orthogonal approach of PPI stabilization lacks establ…
View article: Reversible Covalent Imine-Tethering for Selective Stabilization of 14-3-3 Hub Protein Interactions
Reversible Covalent Imine-Tethering for Selective Stabilization of 14-3-3 Hub Protein Interactions Open
The stabilization of protein complexes has emerged as a promising modality, expanding the number of entry points for novel therapeutic intervention. Targeting proteins that mediate protein-protein interactions (PPIs), such as hub proteins,…
View article: Structure–Activity Relationship Studies of Trisubstituted Isoxazoles as Selective Allosteric Ligands for the Retinoic-Acid-Receptor-Related Orphan Receptor γt
Structure–Activity Relationship Studies of Trisubstituted Isoxazoles as Selective Allosteric Ligands for the Retinoic-Acid-Receptor-Related Orphan Receptor γt Open
The inhibition of the nuclear receptor retinoic-acid-receptor-related orphan receptor γt (RORγt) is a promising strategy in the treatment of autoimmune diseases. RORγt features an allosteric binding site within its ligand-binding domain th…
View article: Covalent Flexible Peptide Docking in Rosetta
Covalent Flexible Peptide Docking in Rosetta Open
Electrophilic peptides that form an irreversible covalent bond with their target have great potential for binding targets that have been previously considered undruggable. However, the discovery of such peptides remains a challenge. Here, …
View article: Covalent flexible peptide docking in Rosetta
Covalent flexible peptide docking in Rosetta Open
We developed Rosetta CovPepDock, a computational pipeline for covalent peptide docking. We showed it is highly accurate in retrospective benchmarks, and applied it prospectively to design potent and selective covalent binders of 14-3-3σ.
View article: Fragment‐Based Stabilizers of Protein–Protein Interactions through Imine‐Based Tethering
Fragment‐Based Stabilizers of Protein–Protein Interactions through Imine‐Based Tethering Open
Small‐molecule stabilization of protein–protein interactions (PPIs) is a promising concept in drug discovery, however the question how to identify or design chemical starting points in a “bottom‐up” approach is largely unanswered. We repor…
View article: Fragment‐Based Stabilizers of Protein–Protein Interactions through Imine‐Based Tethering
Fragment‐Based Stabilizers of Protein–Protein Interactions through Imine‐Based Tethering Open
Small‐molecule stabilization of protein–protein interactions (PPIs) is a promising concept in drug discovery, however the question how to identify or design chemical starting points in a “bottom‐up” approach is largely unanswered. We repor…
View article: <i>In situ</i> epoxide generation by dimethyldioxirane oxidation and the use of epichlorohydrin in the flow synthesis of a library of β-amino alcohols
<i>In situ</i> epoxide generation by dimethyldioxirane oxidation and the use of epichlorohydrin in the flow synthesis of a library of β-amino alcohols Open
The flow coupling of epichlorohydrin with substituted phenols, while efficient, limits the nature of the epoxide available for the development of focused libraries of β-amino alcohols. This limitation was encountered in the production of a…
View article: Supplementary material from "<i>In situ</i> epoxide generation by dimethyldioxirane oxidation and the use of epichlorohydrin in the flow synthesis of a library of β-amino alcohols"
Supplementary material from "<i>In situ</i> epoxide generation by dimethyldioxirane oxidation and the use of epichlorohydrin in the flow synthesis of a library of β-amino alcohols" Open
The flow coupling of epichlorohydrin with substituted phenols, while efficient, limits the nature of the epoxide available for the development of focused libraries of β-amino alcohols. This limitation was encountered in the production of a…
View article: Small-Molecule Inhibitors of the NusB–NusE Protein–Protein Interaction with Antibiotic Activity
Small-Molecule Inhibitors of the NusB–NusE Protein–Protein Interaction with Antibiotic Activity Open
The NusB-NusE protein-protein interaction (PPI) is critical to the formation of stable antitermination complexes required for stable RNA transcription in all bacteria. This PPI is an emerging antibacterial drug target. Pharmacophore-based …