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Synthesis and Biological Evaluation of β-hairpin Peptides as Covalent Inhibitors of the PD-1/PD-L1 Immune Checkpoint
Title
Synthesis and Biological Evaluation of β-hairpin Peptides as Covalent Inhibitors of the PD-1/PD-L1 Immune Checkpoint.
Creator
Naylon, Sarah, Roche, Stephane, Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
Abstract/Description
Protein─protein interactions (PPIs) are essential for cell─cell interactions and cellular signal transduction, which play a crucial role in various human diseases. PPIs involved in cancer immunology pathways, known as immune checkpoints, have been intensely studied, leading to a new approach to cancer therapy. The PD1:PDL1 interaction is one of the most essential immune checkpoints. Studies on PD1:PDL1 showed over ten clinical monoclonal antibodies (mAb) used to treat cancer patients....
Show moreProtein─protein interactions (PPIs) are essential for cell─cell interactions and cellular signal transduction, which play a crucial role in various human diseases. PPIs involved in cancer immunology pathways, known as immune checkpoints, have been intensely studied, leading to a new approach to cancer therapy. The PD1:PDL1 interaction is one of the most essential immune checkpoints. Studies on PD1:PDL1 showed over ten clinical monoclonal antibodies (mAb) used to treat cancer patients. Unfortunately, antibodies do not penetrate the tumor microenvironment well, and clearance from the body is slow, leading to unwanted side effects. There is a significant gap in the drug market between the typical Rule of 5 (Ro5) small-molecule drugs (MW<0.5 kDa, SASA ~150 Å) and large antibodies with molecular weights greater than 40 kDa (SASA >2,000 Å). PPIs remain challenging to modulate by small molecules due to their large, shallow, often dynamic, and water-exposed surfaces lacking well-defined binding pockets. Thus, our lab was drawn to work on large β-hairpin peptides (2-3 kDa) that can potentially mimic the CDR-H3 loops of some of the most potent and clinical anti-PD1 antibodies. Exploration of these β-hairpin peptides provided valuable insights into their folding stability, conformational flexibility, passive membrane permeability, and protein-protein interaction (PPI) blocking activities. Additionally, the rational design of TCIs against PD1, specifically targeting a lysine residue, emerged as a strategy to irreversibly obstruct the PD1:PDL1 protein-protein interaction enhancing potency of the non-covalent inhibitors by taking advantage of their specificity. Meticulous structural analysis, peptide synthesis, and biological evaluations are presented contributing comprehensions into covalent inhibitor development of drugs fbRo5.
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Date Issued
2023
PURL
http://purl.flvc.org/fau/fd/FA00014353
Subject Headings
Cancer--Immunological aspects, Protein-protein interactions, Antibodies, Monoclonal
Format
Document (PDF)
A Study on Reversing the Immunosuppressive Phenotype of Tumor Associated Macrophages
Title
A Study on Reversing the Immunosuppressive Phenotype of Tumor Associated Macrophages.
Creator
Liddle, Genevieve M., Hartmann, James X., Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
Abstract/Description
Extracellular stimuli may influence the M1/M2 phenotypic polarization of macrophages. We examined M1/M2 biomarkers, phagocytic activity, and tumoricidal activity in RAW 264.7 mouse macrophages. Macrophages were treated with conditioned media (CM) from 4T1 breast cancer cells, curcumin, 22-oxacalcitriol, LPS, or a combination of the previously listed. Arginase activity, a M2 phenotypic biomarker, was upregulated by the treatment of macrophages with conditioned media. Curcumin, 22-...
Show moreExtracellular stimuli may influence the M1/M2 phenotypic polarization of macrophages. We examined M1/M2 biomarkers, phagocytic activity, and tumoricidal activity in RAW 264.7 mouse macrophages. Macrophages were treated with conditioned media (CM) from 4T1 breast cancer cells, curcumin, 22-oxacalcitriol, LPS, or a combination of the previously listed. Arginase activity, a M2 phenotypic biomarker, was upregulated by the treatment of macrophages with conditioned media. Curcumin, 22- oxacalcitriol, and LPS partially inhibited RAW 264.7 arginase activity in the presence of 4T1 breast cancer media. 22-oxacalcitriol increased the phagocytic ability of RAW 264.7 macrophages in the presence of M2 polarizing substances produced by the 4T1 breast cancer cells. Also, LPS increased RAW 264.7 phagocytic ability in the presence of 4T1 breast cancer CM. This study looked at the potential substances that would possibly reverse the M2 tumor promoting macrophage phenotype seen in the breast cancer tumor environment.
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Date Issued
2017
PURL
http://purl.flvc.org/fau/fd/FA00004867
Subject Headings
Macrophages., Breast--Cancer--Treatment., Tumors--Immunological aspects., Cancer--Immunological aspects., Biological response modifiers., Cancer--Molecular aspects.
Format
Document (PDF)