biostudies-literatureHawley KMAmerican Cancer SocietyHyundai Hope on WheelsUniversity of Chicago Cancer Biology training grantNCI NIH HHSLois R. and Maurice J. BeznosComer Children's Hospital, University of Chicago MedicineMSTP training grantNIGMS NIH HHSNIH F30 Fellowshipe2209044119https://www.ebi.ac.uk/biostudies/studies/S-EPMC9586281biostudies-literatureUnknown119(42)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 Proceedings of the National Academy of Sciences of the United States of AmericaInhibition of FOXP3 by stapled alpha-helical peptides dampens regulatory T cell function.PMC9586281R50 CA211399N/AF30CA221250F30 CA221250T32 CA009594R35 CA197583T32CA009594T32GM007281P30 CA014599T32 GM007281Fefferman MSchnorenberg MRShah RNEclov RJBird GHTian YHawley KMWalensky LDTirrell MVThomas-Toth ATLaBelle JLfalseInhibition of FOXP3 by stapled alpha-helical peptides dampens regulatory T cell function.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 2022-01-01T00:00:00Z2022 Oct2026-05-28T01:04:34.574Z2025-04-19T22:48:18.204ZS-EPMC95862813622791710.1073/pnas.2209044119