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FOXP3 Stapled Peptides to Deactivate Regulatory T Cells
University of Chicago
Peptide
Immunology
Hit To Lead or Lead Optimization
• Stapled alpha-helical peptides (SAHs) in the likeness of a portion of the native FOXP3 antiparallel coiled-coil homodimerization domain (SAHFOXP3) block this key FOXP3 protein-protein interaction (PPI) through molecular mimicry.
• Regulatory T cells (Tregs) modulate immune function by preventing autoreactive T cell responses, including those that would normally target cancer cells. Treg activity can significantly limit the efficacy of immunotherapies designed to stimulate CD8+ T cells, and therefore a strategy for reducing Treg activity as an aspect of immunotherapy is highly desirable.
• The FOXP3 transcription factor is selectively expressed in Tregs and is necessary for Treg function. The inventors have synthesized stapled alpha helix peptides that inhibit the FOXP3 homo and heterodimerization necessary to form a functional complex. These peptides block FOXP3 signaling, and consequently indirectly inhibit Treg function.
• The product is (1) stapled alpha helix peptides that inhibit FOXP3 transcriptional activity and (2) intracellular delivery of the stapled alpha helix peptides using targeted nanoparticles. • In initial proof-of-concept studies, the stapled alpha helix peptides bound to recombinant FOXP3 with nanomolar affinity and reduced expression of FOXP3 regulated genes.
US20210094990A1
Inhibition of FOXP3 by stapled alpha-helical peptides dampens regulatory T cell function. PNAS, (2022)
