Ribosome-mediated polymerization of long chain carbon and cyclic amino acids into peptides in vitro

TL;DR

Scientists designed special amino acids to work with ribosomes, enabling the creation of new peptides that could lead to novel medicines and materials.

Contribution

The study introduces non-canonical amino acid analogs with extended carbon chains or cyclic structures for improved ribosome compatibility and tRNA charging.

Findings

Non-canonical amino acid analogs with extended carbon chains or cyclic structures were successfully incorporated into peptides.

Engineered ribosomes enabled site-specific incorporation of backbone-extended monomers at the N- and C-terminus of peptides.

This approach expands the potential of ribosome-mediated polymerization for new applications in medicine and materials.

Abstract

Ribosome-mediated polymerization of backbone-extended monomers into polypeptides is challenging due to their poor compatibility with the translation apparatus, which evolved to use α-L-amino acids. Moreover, mechanisms to acylate (or charge) these monomers to transfer RNAs (tRNAs) to make aminoacyl-tRNA substrates is a bottleneck. Here, we rationally design non-canonical amino acid analogs with extended carbon chains (γ-, δ-, ε-, and ζ-) or cyclic structures (cyclobutane, cyclopentane, and cyclohexane) to improve tRNA charging. We then demonstrate site-specific incorporation of these non-canonical, backbone-extended monomers at the N- and C- terminus of peptides using wild-type and engineered ribosomes. This work expands the scope of ribosome-mediated polymerization, setting the stage for new medicines and materials.

Backbone extended monomers are poorly compatible with the natural ribosomes, impeding their polymerization into polypeptides. Here the authors design non-canonical amino acid analogs with cyclic structures or extended carbon chains and used an engineered ribosome to improve tRNA-charging and incorporation into peptides.

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