8QFZ

TSLP-Bicycle complex

8QFZ の概要

• エントリーDOI: 10.2210/pdb8qfz/pdb
• 分子名称: Thymic stromal lymphopoietin, CYS-HIS-TRP-LEU-GLU-ASN-CYS-TRP-ARG-GLY-PHE-CYS, 1-[3,5-bis(3-bromanylpropanoyl)-1,3,5-triazinan-1-yl]-3-bromanyl-propan-1-one, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, hormone
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 16631.69

構造登録者

Petersen, J. (登録日: 2023-09-05, 公開日: 2024-02-07, 最終更新日: 2024-10-23)

主引用文献

Narjes, F.,Edfeldt, F.,Petersen, J.,Oster, L.,Hamblet, C.,Bird, J.,Bold, P.,Rae, R.,Back, E.,Stomilovic, S.,Zlatoidsky, P.,Svensson, T.,Hidestal, L.,Kunalingam, L.,Shamovsky, I.,De Maria, L.,Gordon, E.,Lewis, R.J.,Watcham, S.,van Rietschoten, K.,Mudd, G.E.,Harrison, H.,Chen, L.,Skynner, M.J.
Discovery and Characterization of a Bicyclic Peptide (Bicycle) Binder to Thymic Stromal Lymphopoietin.
J.Med.Chem., 67:2220-2235, 2024

PubMed Abstract: Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pro-inflammatory cytokine involved in the development of asthma and other atopic diseases. We used Bicycle Therapeutics' proprietary phage display platform to identify bicyclic peptides (Bicycles) with high affinity for TSLP, a target that is difficult to drug with conventional small molecules due to the extended protein-protein interactions it forms with both receptors. The hit series was shown to bind to TSLP in a hotspot, that is also used by IL-7Rα. Guided by the first X-ray crystal structure of a small peptide binding to TSLP and the identification of key metabolites, we were able to improve the proteolytic stability of this series in lung S9 fractions without sacrificing binding affinity. This resulted in the potent Bicycle with nanomolar affinity to TSLP ( = 13 nM), low plasma clearance of 6.4 mL/min/kg, and an effective half-life of 46 min after intravenous dosing to rats.

PubMed: 38284169
DOI: 10.1021/acs.jmedchem.3c02163

実験手法

X-RAY DIFFRACTION (1.65 Å)