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조회313

한국과학기술연구원

Adv. Sci., Oct 31 2024, | https://doi.org/10.1002/advs.202406018 Massively Parallel Screening of Toll/Interleukin-1 Receptor (TIR)-Derived Peptides Reveals Multiple Toll-Like Receptors (TLRs)-Targeting Immunomodulatory Peptides

Yun Lim ¹, Tae Kyeom Kang ¹, Meong Il Kim ¹, Dohyeon Kim ^2,3, Ji Yul Kim ^1,4, Sang Hoon Jung ¹, Keunwan Park^2,5, Wook-Bin Lee ^1,5, Moon-Hyeong Seo ^1,4

¹Natural Product Research Center, Korea Institute of Science and Technology, Gangneung, 25451, Republic of Korea.

²Natural Product Informatics Research Center, Korea Institute of Science and Technology, Gangneung, 25451, Republic of Korea.

³Department of Bioinformatics and Life Science, Soongsil University, Seoul, 06978, Republic of Korea.

⁴Department of Convergence Medicine, Yonsei University Wonju College of Medicine, Wonju, 26426, Republic of Korea.

⁵Department of YM-KIST Bio-Health Convergence, Yonsei University, Wonju, 26493, Republic of Korea.

Y.L. and T.K.K. contributed equally to this work.

Corresponding Authors : Keunwan Park, Wook-Bin Lee, Moon-Hyeong Seo

Abstract

Toll-like receptors (TLRs) are critical regulators of the immune system, and altered TLR responses lead to a variety of inflammatory diseases. Interference of intracellular TLR signaling, which is mediated by multiple Toll/interleukin-1 receptor (TIR) domains on all TLRs and TLR adapters, is an effective therapeutic strategy against immune dysregulation. Peptides that inhibit TIR-TIR interactions by fragmenting interface residues have potential as therapeutic decoys. However, a systematic method for discovering TIR-targeting moieties has been elusive, limiting exploration of the vast, unsequenced space of the TIR domain family. A comprehensive parallel screening method is developed to uncover novel TIR-binding peptides derived from previously unexplored surfaces on a wide range of TIR domains. A large peptide library is constructed, named TIR surfacesome, by tiling surface sequences of the large TIR domain family and screening against MAL^TIR and MyD88^TIR, TIRs of two major TLR adaptor proteins, resulting in the discovery of hundreds of TIR-binding peptides. The selected peptides inhibited TLR signaling and demonstrated anti-inflammatory effects in macrophages, and therapeutic potential in mouse inflammatory models. This approach may facilitate the development of TLR-targeted therapeutics.

논문정보

형식Research article
게재일2024년 10월 (BRIC 등록일 2024-11-04)
연구진국내 연구진
분야 생명과학 > 생물공학

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