8qfz | pdb_00008qfz
TSLP-Bicycle complex
Structural highlights
FunctionTSLP_HUMAN Isoform 1: Cytokine that induces the release of T-cell-attracting chemokines from monocytes and, in particular, enhances the maturation of CD11c(+) dendritic cells. Can induce allergic inflammation by directly activating mast cells.[1] [2] [3] Isoform 2: May act as an antimicrobial peptide in the oral cavity and on the skin.[4] Publication Abstract from PubMedThymic 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-7Ralpha. 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 46 with nanomolar affinity to TSLP (K(D) = 13 nM), low plasma clearance of 6.4 mL/min/kg, and an effective half-life of 46 min after intravenous dosing to rats. Discovery and Characterization of a Bicyclic Peptide (Bicycle) Binder to Thymic Stromal Lymphopoietin.,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 RJ, Watcham S, van Rietschoten K, Mudd GE, Harrison H, Chen L, Skynner MJ J Med Chem. 2024 Feb 8;67(3):2220-2235. doi: 10.1021/acs.jmedchem.3c02163. Epub , 2024 Jan 29. PMID:38284169[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
