Prof. Jan van Maarseveen of Bio-inspired Synthetic Chemistry was invited by Nature Chemistry to provide a perspective on creating interlocked molecules by tying peptide ropes, using a chemical as well as a biological toolbox.
Van Maarseveen wrote his contribution to the 'news and views' section of Nature's chemistry journal in reference to a paper from the group of Prof. James Link at Princeton University. This presents a creative semi-synthesis of peptide mechanically interlocked molecules, starting from recombinantly produced lasso peptide analogues. In particular, the paper reports the synthesis of a peptidic [c2]daisy chain that may find application in devices to mimic the contraction of natural muscles.
The two-page article by Prof. Van Maarseveen provides an overview of the current state of lasso peptide science, the field in which his group is also active, and puts the accomplishment of the Link group in perspective. He writes that the combination of biosynthetical and chemical techniques opens up interesting horizons in exploring the potential of the pharmacologically promising lasso peptides, for instance with respect to enhancing biological activity and establishing stability against metabolic degradation. In his view, lasso peptides provide extraordinary challenges to the synthetic chemistry community even though a practical and generally applicable chemical method for their total synthesis most probably lies far in the future. The crux of these challenges does not stem from the development of novel methodologies to make bonds, but from the precise regio- and stereoselective folding of a linear precursor into the structurally dense and mechanically chiral lariat conformation, using bio-inspired templates that are either supramolecular or covalent in nature. Furthermore, chemical methods are more scalable and allow for a far wider molecular diversity than the biological toolbox, which is limited to the 20 canonical amino acids and some non-natural analogues introduced by recombinant tweaking.
Van Maarseveen remarks that lasso peptides will most certainly remain a fruitful research target that encourages collaborations in many fields, including synthetic biology, chemical synthesis, computational chemistry, and pharmacochemistry. And as he writes in his accompanying LinkedIn post: "I sincerely hope more groups will embark on the synthesis of these extremely challenging, aesthetic and promising molecules."
Van Maarseveen, J.H.: Tying peptide ropes. Nat. Chem. (2021) Published 23 August 2021. DOI: 10.1038/s41557-021-00771-6
Visit the website of the research group of Prof. Van Maarseveen.