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

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 K-D=4-6 mu M 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 (N-3-PEG(6)-NMe17A2) showed retention in circulation similar to SA-21; in contrast, apelin-17 analogue was cleared from the circulation after 2min. 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.

Automated summary

Peptide-based therapeutics with poor circulation half-life have been a challenge. In this study, researchers successfully selected albumin-binding macrocyclic peptides from genetically encoded libraries modified by specific chemistry. The selected peptides showed high affinity for human serum albumin and demonstrated longer in vivo circulation half-life, which is a promising starting point for developing compact macrocycles with extended half-life.