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Helical polymers for biological and medical applications

Abstract

Helices are the most prevalent secondary structure in biomolecules and play vital roles in their activity. Chemists have been fascinated with mimicking this molecular conformation with synthetic materials. Research has now been devoted to the synthesis and characterization of helical materials, and to understand the design principles behind this molecular architecture. In parallel, work has been done to develop synthetic polymers for biological and medical applications. We now have access to materials with controlled size, molecular conformation, multivalency or functionality. As a result, synthetic polymers are being investigated in areas such as drug and gene delivery, tissue engineering, imaging and sensing, or as polymer therapeutics. Here, we provide a critical view of where these two fields, helical polymers and polymers for biological and medical applications, overlap. We have selected relevant polymer families and examples to illustrate the range of applications that can be targeted and the impact of the helical conformation on the performance. For each family of polymers, we briefly describe how they can be prepared, what helical conformations are observed and what parameters control helicity. We close this Review with an outlook of the challenges ahead, including the characterization of helicity through the process and the identification of biocompatibility.

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Fig. 1: Major families of helical polymers discussed in this Review.
Fig. 2: Controlling helical conformation in poly(amino acid)s.
Fig. 3: Antimicrobial and gene-delivery applications of poly(amino acid)s.
Fig. 4: Helical poly(amino acid)s for drug delivery.
Fig. 5: Hydrogels formed from helical polymers.
Fig. 6: Vesicles based on poly(isocyanide)s for nanoreactors and artificial organelles.
Fig. 7: Modulation of helical chirality in poly(acetylene)s through external stimuli.
Fig. 8: The application of helical poly(thiophene)s in biosensing.

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Acknowledgements

P.F.-T. thanks the University of Birmingham for the John Evans Fellowship. T.L. gratefully acknowledges financial support from the Engineering and Physical Sciences Research Council (EPSRC) through a studentship from the Centre for Doctoral Training in Physical Sciences for Health (EP/L016346/1).

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T.L. and P.F.-T. reviewed the literature, organized the Review and designed the figures. P.F.-T. wrote the manuscript, with both authors contributing to the final version of the Review.

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Correspondence to Paco Fernandez-Trillo.

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Glossary

Secondary structure

The conformational arrangement (α-helix, β-pleated sheet etc.) of the backbone segments of a macromolecule, such as a polypeptide chain of a protein, without regard to the conformation of the side chains or the relationship to other segments.

Helicity

The chirality of a helical, propeller or screw-shaped molecular entity.

Helix

The molecular conformation of a spiral nature, generated by regularly repeating rotations around the backbone bonds of a macromolecule.

Helical sense

The sense of rotation around the helical axis. Viewing from either end of a molecule downwards along the helical axis, the system has P helicity (or plus) if the rotation is clockwise (or right-handed) and M helicity (or minus) if the rotation is anticlockwise (or left-handed).

Drug delivery

The translocation of a therapeutic agent to the site of activity or infection.

Gram-negative bacteria

Bacteria that have a thin peptidoglycan layer and an outer lipid membrane.

Gram-positive bacteria

Bacteria that have a thick peptidoglycan layer and no outer lipid membrane.

Gene delivery

A process by which foreign genetic material, for example, DNA or RNA, is transferred to host cells for applications such as genetic research or gene therapy. Gene delivery can result in multiple effects, including gene knockdown, i.e. the deactivation or suppression of a gene, gene knockin, i.e. the one-for-one substitution of a gene into a host’s genome, or gene knockout, i.e. the total removal or permanent deactivation of a gene.

Gene knockdown

The deactivation or suppression of a gene.

Helical pitch

Also known as (chain) identity period or (chain) conformational repeating unit. The distance or number of residues along the chain axis for a complete turn. This conformational unit is repeated along the chain through symmetry operations. In an α-helix formed from α-amino acids, there are 3.6 residues per ‘turn’, with a 5.4-angstroms turn.

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Leigh, T., Fernandez-Trillo, P. Helical polymers for biological and medical applications. Nat Rev Chem 4, 291–310 (2020). https://doi.org/10.1038/s41570-020-0180-5

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