What is a Foldamer?

According to Samuel H. Gellman (1998), a foldamer is any polymer that has a strong tendency to adopt a specific compact conformation. Foldamers are artificial oligomers with high conformational stability and structural predictability. Correctly designed foldamers can mimic protein secondary structures such as helices or sheets as well as ribbons. 

However, Hill et al. define a foldamer as any oligomer that folds into a conformationally ordered state in solution. Foldamers refer to structures stabilized by a collection of noncovalent interactions between nonadjacent monomer units. 

According to Hill et al. (2001), there are two major classes of foldamers

(1) single-stranded foldamers that only fold such as peptidomimetics and their abiotic analogs, and 

(2) multiple-stranded foldamers that both associate and fold, such as nucleotide mimetics and their synthetic analogs. 

Next, Nandity and Fülöp (2015) define foldamers as follows 

Foldamers are artificial self-organizing systems with various critical properties: 

  • a stable and designable secondary structure; 

  • a larger molecular surface as compared with ordinary organic drug molecules; 

  • appropriate control of the orientation of the side-chain functional groups; 

  • resistance against proteolytic degradation, which leads to potentially increased oral bioavailability and a longer serum half-life relative to ordinary α-peptides; and 

  • the lower conformational freedom may result in increased receptor binding in comparison with the natural analogs.”

General principles essential for the design of foldamers according to Gellman are the

  • Hierarchical organization of conformation such as secondary structure, the local conformational preferences of the poly(α-amino acid) backbone, versus tertiary structure, how various secondary structural elements are packed together. 

  • Cooperativity in higher-order structures.

  • Sequence heterogeneity.


    Gellman, Samuel H.; Foldamers: A Manifesto. Acc. Chem. Res. 1998, 31, 173-180. https://pubs.acs.org/doi/10.1021/ar960298r.

    David J. Hill, Matthew J. Mio, Ryan B. Prince, Thomas S. Hughes, Jeffrey S. Moore; A Field Guide to Foldamers. Chem. Rev. 2001, 101, 12, 3893-4012. Publication Date:December 12, 2001. https://doi.org/10.1021/cr990120t  https://pubs.acs.org/doi/10.1021/cr990120t.

    István M Mándity & Ferenc Fülöp (2015) An overview of peptide and peptoid foldamers in medicinal chemistry, Expert Opinion on Drug Discovery, 10:11, 1163-1177, DOI: 10.1517/17460441.2015.1076790 https://www.ncbi.nlm.nih.gov/pubmed/26289578.