8QFZ

TSLP-Bicycle complex

Summary for 8QFZ

• Entry DOI: 10.2210/pdb8qfz/pdb
• Descriptor: 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)
• Functional Keywords: inhibitor, complex, hormone
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 16631.69

Authors

Petersen, J. (deposition date: 2023-09-05, release date: 2024-02-07, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.65 Å)