Sequence-Specific β‑Peptide Synthesis by a Rotaxane-Based Molecular Machine

• Published in: Journal of the American Chemical Society Vol. 139; no. 31; pp. 10875 - 10879
• Main Authors: De Bo, Guillaume, Gall, Malcolm A. Y, Kitching, Matthew O, Kuschel, Sonja, Leigh, David A, Tetlow, Daniel J, Ward, John W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.08.2017; Amer Chemical Soc
• Subjects: Amino Acid Sequence; Chemistry; Chemistry, Multidisciplinary; Peptides - chemical synthesis; Peptides - chemistry; Physical Sciences; Proton Magnetic Resonance Spectroscopy; Ribosomes - chemistry; Rotaxanes - chemistry; Science & Technology; Tandem Mass Spectrometry; UNNATURAL PEPTIDES; ALPHA-PEPTIDE; DNA TEMPLATES; MULTISTEP ORGANIC-SYNTHESIS; RIBOSOME NOBEL LECTURE; AMINO-ACIDS; PROTEOLYTIC STABILITY; GAMMA-PEPTIDES; CYCLIC TRANSITION-STATES; CHEMICAL LIGATION
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.7b05850

We report on the synthesis and operation of a three-barrier, rotaxane-based, artificial molecular machine capable of sequence-specific β-homo (β3) peptide synthesis. The machine utilizes nonproteinogenic β3-amino acids, a class of amino acids not generally accepted by the ribosome, particularly consecutively. Successful operation of the machine via native chemical ligation (NCL) demonstrates that even challenging 15- and 19-membered ligation transition states are suitable for information translation using this artificial molecular machine. The peptide-bond-forming catalyst region can be removed from the transcribed peptide by peptidases, artificial and biomachines working in concert to generate a product that cannot be made by either machine alone.