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- Title
Genetically encoded discovery of perfluoroaryl macrocycles that bind to albumin and exhibit extended circulation in vivo.
- Authors
Wong, Jeffrey Y. K.; Ekanayake, Arunika I.; Kharchenko, Serhii; Kirberger, Steven E.; Qiu, Ryan; Kelich, Payam; Sarkar, Susmita; Li, Jianqian; Fernandez, Kleinberg X.; Alvizo-Paez, Edgar R.; Miao, Jiayuan; Kalhor-Monfared, Shiva; John, J. Dwyer; Kang, Hongsuk; Choi, Hwanho; Nuss, John M.; Vederas, John C.; Lin, Yu-Shan; Macauley, Matthew S.; Vukovic, Lela
- Abstract
Peptide-based therapeutics have gained attention as promising therapeutic modalities, however, their prevalent drawback is poor circulation half-life in vivo. In this paper, we report the selection of albumin-binding macrocyclic peptides from genetically encoded libraries of peptides modified by perfluoroaryl-cysteine SNAr chemistry, with decafluoro-diphenylsulfone (DFS). Testing of the binding of the selected peptides to albumin identified SICRFFC as the lead sequence. We replaced DFS with isosteric pentafluorophenyl sulfide (PFS) and the PFS-SICRFFCGG exhibited KD = 4–6 µM towards human serum albumin. When injected in mice, the concentration of the PFS-SICRFFCGG in plasma was indistinguishable from the reference peptide, SA-21. More importantly, a conjugate of PFS-SICRFFCGG and peptide apelin-17 analogue (N3-PEG6-NMe17A2) showed retention in circulation similar to SA-21; in contrast, apelin-17 analogue was cleared from the circulation after 2 min. The PFS-SICRFFC is the smallest known peptide macrocycle with a significant affinity for human albumin and substantial in vivo circulation half-life. It is a productive starting point for future development of compact macrocycles with extended half-life in vivo. Peptide-based therapeutics are promising therapeutic modalities, however, their prevalent drawback is poor circulation half-life in vivo. Here, the authors report the selection of albumin-binding macrocyclic peptides from genetically encoded libraries of peptides modified by perfluoroaryl-cysteine chemistry, with decafluoro-diphenylsulfone.
- Subjects
PEPTIDES
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-41427-y