ArticleProceedings of the National Academy of Sciences of the United States of America2022
Inhibition of FOXP3 by stapled alpha-helical peptides dampens regulatory T cell function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
What it found
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Who cites it
13 citing papers in PubMed, 14 citations in OpenAlex.
- Targeting LKB1-inactivated lung cancers with a stapled peptide inhibitor of the CRTC-CREB pathway.Molecular therapy. Oncology · 2026Article
- Transcription factors remodel tumor immune microenvironment by impacting multiple immune cells.Discover oncology · 2026Review
- α-Helical peptides: design strategies and recent advances in biomedical applications.Journal of translational medicine · 2026Review
- Regulatory T cell dysfunction and exhaustion in uveitis: immunometabolic mechanisms, microenvironmental drivers, and emerging therapeutic strategies.Frontiers in immunology · 2026Review
- Targeted protein degradation dismantles undruggable targets to reverse immune evasion and therapy resistance in cancer.Frontiers in immunology · 2026Review
- The structure of a NEMO construct engineered for screening reveals novel determinants of inhibition.Structure (London, England : 1993) · 2025Article
- Pseudokinase TRIB3 stabilizes SSRP1 via USP10-mediated deubiquitination to promote multiple myeloma progression.Oncogene · 2025Article
- Selection of Nucleotide-Encoded Mass Libraries of Macrocyclic Peptides for Inaccessible Drug Targets.Chemical reviews · 2024Review
- The Role of Structural Flexibility in Hydrocarbon-Stapled Peptides Designed to Block Viral Infection via Human ACE2 Mimicry.Peptide science (Hoboken, N.J.) · 2024Article
- Advances in Foxp3+ regulatory T cells (Foxp3+ Treg) and key factors in digestive malignancies.Frontiers in immunology · 2024Review
- Stabilized cyclic peptides as modulators of protein-protein interactions: promising strategies and biological evaluation.RSC medicinal chemistry · 2023Review
- Effect of Radio-Chemotherapy on PD-L1 Immunohistochemical Expression in Head and Neck Squamous Cell Carcinoma.Journal of personalized medicine · 2023Review
- Inhibition of FOXP3 by stapled alpha-helical peptides dampens regulatory T cell function.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Despite continuing advances in the development of novel cellular-, antibody-, and chemotherapeutic-based strategies to enhance immune reactivity, the presence of regulatory T cells (Treg cells) remains a complicating factor for their clinical efficacy. To overcome dosing limitations and off-target effects from antibody-based Treg cell deletional strategies or small molecule drugging, we investigated the ability of hydrocarbon stapled alpha-helical (SAH) peptides to target FOXP3, the master transcription factor regulator of Treg cell development, maintenance, and suppressive function. Using the crystal structure of the FOXP3 homodimer as a guide, we developed SAHs in the likeness of a portion of the native FOXP3 antiparallel coiled-coil homodimerization domain (SAH-FOXP3) to block this key FOXP3 protein-protein interaction (PPI) through molecular mimicry. We describe the design, synthesis, and biochemical evaluation of single- and double-stapled SAHs covering the entire coiled-coil expanse. We show that lead SAH-FOXP3s bind FOXP3, are cell permeable and nontoxic to T cells, induce dose-dependent transcript and protein level alterations of FOXP3 target genes, impede Treg cell function, and lead to Treg cell gene expression changes in vivo consistent with FOXP3 dysfunction. These results demonstrate a proof of concept for rationally designed FOXP3-directed peptide therapeutics that could be used as approaches to amplify endogenous immune responsiveness.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.