9gh7 | pdb_00009gh7
Complex of human TfR1 with a potent bicyclic peptide
Structural highlights
FunctionTFR1_HUMAN Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes. Endosomal acidification leads to iron release. The apotransferrin-receptor complex is then recycled to the cell surface with a return to neutral pH and the concomitant loss of affinity of apotransferrin for its receptor. Transferrin receptor is necessary for development of erythrocytes and the nervous system (By similarity). A second ligand, the heditary hemochromatosis protein HFE, competes for binding with transferrin for an overlapping C-terminal binding site.[1] Publication Abstract from PubMedImproving 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(R) molecule BCY17901), with a molecular weight of approximately 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. Conjugation to a transferrin receptor 1-binding Bicycle peptide enhances ASO and siRNA potency in skeletal and cardiac muscles.,Ostergaard ME, Carrer M, Anderson BA, Afetian M, Bakooshli MA, Santos JA, Klein SK, Capitanio J, Freestone GC, Tanowitz M, Galindo-Murillo R, Gaus HJ, Dwyer CA, Jackson M, Jafar-Nejad P, Rigo F, Seth PP, Gaynor KU, Stanway SJ, Urbonas L, St Denis MA, Pellegrino S, Bezerra GA, Rigby M, Gowans E, Van Rietschoten K, Beswick P, Chen L, Skynner MJ, Swayze EE Nucleic Acids Res. 2025 Apr 10;53(7):gkaf270. doi: 10.1093/nar/gkaf270. PMID:40207629[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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