Current research

Origin of Life
How life emerged from simple non-living chemistry on Earth remains one of the central questions in biology. Modern life relies on the mutual synthesis of proteins (RNA polymerases) and RNA (ribosomes), yet both are large molecular complexes whose origins are poorly understood. To address this question, we are reconstructing evolutionary intermediates between simple peptides and modern RNA polymerases. We have shown that simple positively charged peptides can enhance RNA enzyme activity (Tagami et al., Nat Chem, 2017) and that self-organizing peptides can adsorb and concentrate RNA (Li et al., Nat Commun, 2022). We also reconstructed the core fold of RNA polymerase using peptides composed of only seven amino acid types (Yagi et al., JACS, 2021). Furthermore, we demonstrated that simple mutations in this RNA polymerase core fold can generate structurally distinct protein folds conserved in ribosomal and other proteins, providing experimental insight into how diverse protein folds involved in the central dogma may have evolved from common ancestral peptides (Yagi et al., Nat Commun, 2024). More recently, we identified unusually simple RNA polymerases from thermophilic bacteriophages that may serve as models for ancient RNA polymerases and analyzed their molecular structures (Chaban et al., Nat Commun, 2024).

Peptides with Special Modifications
Modified and cyclized peptides are promising scaffolds for next-generation drug discovery due to their high stability and specificity. Lasso peptides are bacterial antibiotic peptides characterized by a unique threaded rotaxane structure formed through the coordinated action of the maturation proteins B1, B2, and C, although the mechanism of this process has remained unclear. To elucidate the lasso peptide maturation process, we determined the crystal structure of the B1 protein complexed with the precursor peptide (Sumida et al., ACS Chem Biol, 2019). We further performed rapid mutational analysis of B2 using a cell-free translation system combined with structure predictions by AI, identifying a critical hydrophobic interaction surface with B1 (Alfi et al., ACS Synth Biol, 2022). More recently, we identified a widespread RiPP family in Bacillota, termed linear polyphosphorylated peptides (LPPs), whose biosynthetic pathways often occur adjacent to lasso peptide systems. We further showed that their RiPP recognition elements (RREs) selectively recognize cognate precursor peptides, thereby preventing interference between related RiPP pathways (Popov et al., Nat Commun, 2026). We also demonstrated the biomedical potential of lasso peptides by developing a PET imaging probe based on an engineered lasso peptide (Mohri et al., Eur J Pharm Sci, 2023).

Peptide Selection Technologies (Akira Wada)
Based on the molecular evolution of peptides, we have designed and developed in vitro technologies for selecting new peptides that can bind to target molecules of interest. In the process of implementing the technologies, a wide variety of ribosomal complexes were synthesized using cell-free translation system to link 10^12 types of peptides and their corresponding mRNAs. Subsequently, several peptides displayed on the complexes were specifically selected through affinity interactions with target molecules. Finally, target-binding peptides were newly identified by analyzing their mRNAs isolated from the selected complexes. Currently, we aim to create artificially functional peptides as drug candidates using the advanced technologies.