Reflecting recent work in the The Suga Lab

Nonproteinogenic amino acids, including D-α-, β-, and γ-amino acids, present in bioactive peptides play pivotal roles in their biochemical activities and proteolytic stabilities. D-α-Amino acids, DαAA, are widely used building blocks that can enhance the proteolytic stability. Cyclic β^2,3-amino acids, CβAA, for instance, can fold peptides into rigid secondary structures, improving the binding affinity and proteolytic stability.

Cyclic γ^2,4-amino acids, cγAA, are recently highlighted as rigid residues capable of preventing the proteolysis of flanking residues. Simultaneous incorporation of all DαAA, cβAA, and cγAA into a peptide is expected to yield L-α/D-α/β/γ-hybrid peptides with improved stability and potency. Despite challenges in the ribosomal incorporation of multiple nonproteinogenic amino acids, our engineered tRNA^Pro1E2 successfully reaches such a difficulty.

In work published in JACS, researchers in the Suga Group at the University of Tokyo, report the ribosomal synthesis of macrocyclic L-α/D-α/β/γ-hybrid peptide libraries and their application to in vitro selection against interferon gamma receptor 1, IFNGR1.

One of the resulting L-α/D-α/β/γ-hybrid peptides, IB1, exhibited remarkable inhibitory activity against the IFN-γ/IFNGR1 protein–protein interaction, (PPI) (IC₅₀ = 12 nM), primarily attributed to the presence of a cβAA in the sequence. Additionally, cγAAs and DαAAs in the resulting peptides contributed to their serum stability.

Furthermore, our peptides effectively inhibit IFN-γ/IFNGR1 PPI at the cellular level (best IC₅₀ = 0.75 μM). Altogether, our platform expands the chemical space available for exploring peptides with high activity and stability, thereby enhancing their potential for drug discovery.