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INTERLOCKED MOLECULES

Tying peptide ropes

Nature Chemistry volume 13, pages 822–823 (2021)Cite this article

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Although the natural lasso peptide microcin J25 remains an elusive target for total chemical synthesis itself, this topologically non-trivial building block has now been used to construct a range of interlocked molecular architectures including rotaxanes, catenanes and daisy chains.

The biosynthesis of MccJ25 involves several enzymes to facilitate synthesis of the linear ribosomally prepared leader-peptide, folding of the peptide chain into a proto-lasso and finally, locking of the lasso architecture by the formation of an amide bond between the glycine N terminus and the sidechain of a glutamic acid residue5. The resulting 26-membered macrocycle — encircling the C-terminal tail — is small enough that the steric encumberance exerted by the benzylic sidechains of the phenylalanine and tyrosine residues (Fig. 1a; 19 and 20) at each side of the macrocycle prevent the lasso from unthreading. The strength of this natural mechanical bond is exemplified by the survival of MccJ25 in boiling water, even with prolonged exposure5. Cleavage of an amide bond within the lasso loop fragment to afford a peptide [2]rotaxane (Fig. 1b) does not affect the extraordinary strength of this mechanical bond either. The tight binding of the thread into the relatively small ring gives a densely packed globular shape that not only resists thermal decomposition, but also proteolytic degradation. To date, over 80 lasso peptides have been isolated and pharmacological evaluation indicates their potential as antibiotics featuring new modes of action, but also as antiviral and anticancer drugs5.

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Fig. 1: A lasso peptide and its conversion into other structures.

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  1. Van ‘t Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands

    Jan H. van Maarseveen

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  1. Jan H. van Maarseveen
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Correspondence to Jan H. van Maarseveen.

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van Maarseveen, J.H. Tying peptide ropes. Nat. Chem. 13, 822–823 (2021). https://doi.org/10.1038/s41557-021-00771-6

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