Biocompatible strategies for peptide macrocyclisation

Abstract

Peptides are increasingly important drug candidates, offering numerous advantages over conventional small molecules. However, they face significant challenges related to stability, cellular uptake and overall bioavailability. While individual modifications may...

Employing unnatural promiscuity of sortase to construct peptide macrocycle libraries for ligand discovery

“…Although the biotin capture assay cannot assess the following peptide cyclization, the intramolecular reaction between the chloroacetyl group and cysteine residue has proven to be rapid and efficient in many previous studies. 23–36…”

“…20–22 Among them, one of the most widely used approaches is the use of electrophilic reagents to crosslink two or more Cys residues to construct thioether-tethered peptide monocycles or peptide bicycles. 23–36 To ensure the efficiency of the macrocyclization reactions, phage libraries are often treated with highly reactive electrophilic reagents such as benzyl bromide derivatives, which sometimes cause undesired side reactions and phage toxicity. 23,28,29 The embedding of orthogonal reactive non-canonical amino acids (UAAs) is an alternative approach, 37–42 but the incorporation procedure of UAAs is complex.…”

Phage-encoded bismuth bicycles enable instant access to targeted bioactive peptides

“…Integrated into display screening platforms, their vast sequence diversity facilitates the identification of peptide hits for therapeutically relevant targets 4 – 6 . Chemical library modifications compatible with the biological environment of these screening platforms have been shown to enhance the pharmaceutical properties of the displayed peptides 7 – 9 . Particularly desirable are strategies that constrain the entire peptide structure, such as macrocyclisation or bicyclisation 9 – 11 .…”

“…Chemical library modifications compatible with the biological environment of these screening platforms have been shown to enhance the pharmaceutical properties of the displayed peptides 7 – 9 . Particularly desirable are strategies that constrain the entire peptide structure, such as macrocyclisation or bicyclisation 9 – 11 . Restricting the conformational freedom of a peptide can cause dramatic improvement in bioactivity, stability, and membrane permeability 9 , 12 , 13 .…”

“…Particularly desirable are strategies that constrain the entire peptide structure, such as macrocyclisation or bicyclisation 9 – 11 . Restricting the conformational freedom of a peptide can cause dramatic improvement in bioactivity, stability, and membrane permeability 9 , 12 , 13 . Hence, constrained peptides derived from genetically encoded library selections are anticipated to initiate a wave of peptide therapeutics 3 , 14 – 16 .…”