2. Academic Validation
  3. Genetically encoded discovery of perfluoroaryl macrocycles that bind to albumin and exhibit extended circulation in vivo

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

  • Nat Commun. 2023 Sep 13;14(1):5654. doi: 10.1038/s41467-023-41427-y.
Jeffrey Y K Wong # 1,  Arunika I Ekanayake # 1,  Serhii Kharchenko 1,  Steven E Kirberger 2,  Ryan Qiu 1,  Payam Kelich 3,  Susmita Sarkar 1,  Jiaqian Li 2,  Kleinberg X Fernandez 1,  Edgar R Alvizo-Paez 1,  Jiayuan Miao 4,  Shiva Kalhor-Monfared 1,  J Dwyer John 5,  Hongsuk Kang 6,  Hwanho Choi 6,  John M Nuss 5,  John C Vederas 1,  Yu-Shan Lin 4,  Matthew S Macauley 1 7,  Lela Vukovic 3,  William C K Pomerantz 2,  Ratmir Derda 8
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Alberta, Edmonton, AB, T6G 2G2, Canada.
  • 2 Department of Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA.
  • 3 Department of Chemistry and Biochemistry, University of Texas at El Paso, El Paso, TX, 79968, USA.
  • 4 Department of Chemistry, Tufts University, Medford, MA, 02155, USA.
  • 5 Ferring Research Institute, San Diego, CA, 92121, USA.
  • 6 Quantum Intelligence Corp., 31F, One IFC, 10 Gukjegeumyung-ro, Yeongdeungpo-gu-Seoul, Republic of Korea.
  • 7 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, T6G 2E1, Canada.
  • 8 Department of Chemistry, University of Alberta, Edmonton, AB, T6G 2G2, Canada. ratmir@ualberta.ca.
  • # Contributed equally.
PMID: 37704629 DOI: 10.1038/s41467-023-41427-y
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.

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