9GH7

Complex of human TfR1 with a potent bicyclic peptide

これはPDB形式変換不可エントリーです。

9GH7 の概要

• エントリーDOI: 10.2210/pdb9gh7/pdb
• 分子名称: Transferrin receptor protein 1, Bicyclic peptide, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: transferrin receptor protein 1, transport protein
• 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: 78820.96

構造登録者

Pellegrino, S.,Pernigo, S.,Swan, M.K.,Bezerra, G.A.,Chen, L. (登録日: 2024-08-15, 公開日: 2025-04-30)

主引用文献

Ostergaard, M.E.,Carrer, M.,Anderson, B.A.,Afetian, M.,Bakooshli, M.A.,Santos, J.A.,Klein, S.K.,Capitanio, J.,Freestone, G.C.,Tanowitz, M.,Galindo-Murillo, R.,Gaus, H.J.,Dwyer, C.A.,Jackson, M.,Jafar-Nejad, P.,Rigo, F.,Seth, P.P.,Gaynor, K.U.,Stanway, S.J.,Urbonas, L.,St Denis, M.A.,Pellegrino, S.,Bezerra, G.A.,Rigby, M.,Gowans, E.,Van Rietschoten, K.,Beswick, P.,Chen, L.,Skynner, M.J.,Swayze, E.E.
Conjugation to a transferrin receptor 1-binding Bicycle peptide enhances ASO and siRNA potency in skeletal and cardiac muscles.
Nucleic Acids Res., 53:-, 2025

PubMed Abstract: Improving the delivery of antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) to skeletal and cardiac muscles remains a pivotal task toward the broader application of oligonucleotide therapeutics. The targeting of myofibers and cardiomyocytes via conjugation of ASOs and siRNAs to ligands that bind the human transferrin receptor 1 (TfR1) has gathered significant interest in recent years. However, the selection of ligands with low molecular weight and optimal biophysical and binding properties is crucial to maximize the potential of the TfR1 ligand-conjugated antisense (LICA) technology. Here, through effective combination of phage display and peptide medicinal chemistry, we identified and characterized a bicyclic peptide (Bicycle® molecule BCY17901), with a molecular weight of ∼2 kDa, that binds human TfR1 with high affinity and specificity. Conjugation to BCY17901 improved ASO and siRNA potency in skeletal and cardiac muscles of human TfR1 knock-in mice, after either intravenous or subcutaneous administration. Furthermore, single-nucleus RNA sequencing showed that conjugation to BCY17901 enhanced ASO activity in myonuclei of different muscle fiber types. Importantly, we demonstrated good translatability of our TfR1-targeting platform in skeletal and cardiac muscles of nonhuman primates. Our results offer great promise toward potential future applications of low-molecular-weight Bicycle LICA therapeutics for the treatment of diseases affecting skeletal muscle and heart.

PubMed: 40207629
DOI: 10.1093/nar/gkaf270

実験手法

X-RAY DIFFRACTION (2.079 Å)