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
  • 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. [email protected].
  • # 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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