Abstract
Backbone macrocyclic structures are often found in diverse bioactive peptides and contribute to greater conformational rigidity, peptidase resistance, and potential membrane permeability compared to their linear counterparts. Therefore, such peptide scaffolds are an attractive platform for drug-discovery endeavors. Recent advances in synthetic methods for backbone macrocyclic peptides have enabled the discovery of novel peptide drug candidates against diverse targets. Here, we overview recent technical advancements in the synthetic methods including 1) enzymatic synthesis, 2) chemical synthesis, 3) split-intein circular ligation of peptides and proteins (SICLOPPS), and 4) in vitro translation system combined with genetic code reprogramming. We also discuss screening methodologies compatible with those synthetic methodologies, such as one-beads one-compound (OBOC) screening compatible with the synthetic method 2, cell-based assay compatible with 3, limiting-dilution PCR and mRNA display compatible with 4.
Highlights
Peptides have the potential to be therapeutic agents in various aspects
We summarized the applications of solidphase peptide synthesis (SPPS) methods for backbone macrocyclic peptides (Table 1)
Compared with other screening methods such as phage display and individuallysynthesized-peptide-library based drug discovery, OBOC library screening provides a delicate platform for the rapid selection of diverse peptides, incorporating non-proteinogenic amino acids (NAAs), and various chemical modifications including backbone cyclization
Summary
Peptides have the potential to be therapeutic agents in various aspects. Even though they are small in size compared with biological drugs, such as antibodies, they possess unique traits similar to those. The other methods of cyclization use an Backbone Macrocyclic Peptide Synthesis, Screening amino acid’s sidechain.
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