Genetically encoded discovery of perfluoroaryl macrocycles that bind to albumin and exhibit extended circulation in vivo

Jeffrey Y. K. Wong, Arunika I. Ekanayake, Serhii Kharchenko, Steven E. Kirberger, Ryan Qiu, Payam Kelich, Susmita Sarkar, Jiaqian Li, Kleinberg X. Fernandez, Edgar R. Alvizo-Paez, Jiayuan Miao, Shiva Kalhor-Monfared, J. Dwyer John, Hongsuk Kang, Hwanho Choi, John M. Nuss, John C. Vederas, Yu-Shan Lin, Matthew S. Macauley, Lela Vukovic, William C. K. Pomerantz and Ratmir Derda ()
Additional contact information
Jeffrey Y. K. Wong: University of Alberta
Arunika I. Ekanayake: University of Alberta
Serhii Kharchenko: University of Alberta
Steven E. Kirberger: University of Minnesota
Ryan Qiu: University of Alberta
Payam Kelich: University of Texas at El Paso
Susmita Sarkar: University of Alberta
Jiaqian Li: University of Minnesota
Kleinberg X. Fernandez: University of Alberta
Edgar R. Alvizo-Paez: University of Alberta
Jiayuan Miao: Tufts University
Shiva Kalhor-Monfared: University of Alberta
J. Dwyer John: Ferring Research Institute
Hongsuk Kang: Quantum Intelligence Corp., 31F, One IFC
Hwanho Choi: Quantum Intelligence Corp., 31F, One IFC
John M. Nuss: Ferring Research Institute
John C. Vederas: University of Alberta
Yu-Shan Lin: Tufts University
Matthew S. Macauley: University of Alberta
Lela Vukovic: University of Texas at El Paso
William C. K. Pomerantz: University of Minnesota
Ratmir Derda: University of Alberta

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41427-y

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