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Derivatization with fatty acids in peptide and protein drug discovery

Nature Reviews Drug Discovery volume 22, pages 59–80 (2023)Cite this article

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Abstract

Peptides and proteins are widely used to treat a range of medical conditions; however, they often have to be injected and their effects are short-lived. These shortcomings of the native structure can be addressed by molecular engineering, but this is a complex undertaking. A molecular engineering technology initially applied to insulin — and which has now been successfully applied to several biopharmaceuticals — entails the derivatization of peptides and proteins with fatty acids. Various protraction mechanisms are enabled by the specific characteristics and positions of the attached fatty acid. Furthermore, the technology can ensure a long half-life following oral administration of peptide drugs, can alter the distribution of peptides and may hold potential for tissue targeting. Due to the inherent safety and well-defined chemical nature of the fatty acids, this technology provides a versatile approach to peptide and protein drug discovery.

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Fig. 1: Structural elements of a fatty acid protractor moiety.
Fig. 2: Structure of the side chains for biopharmaceuticals based on the fatty acid derivatization technology.
Fig. 3: Selected mechanisms enabled by fatty acid derivatization to extend the half-life of peptide and protein drugs.

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Acknowledgements

This work was funded by Novo Nordisk A/S. The authors thank F. F. Kreiner, Novo Nordisk A/S for outstanding support. They are grateful to the many present and former Novo Nordisk A/S colleagues involved in producing, purifying, quantifying, characterizing and testing some of compounds described in this Review.

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Authors and Affiliations

  1. Novo Nordisk A/S, Bagsværd, Denmark

    Peter Kurtzhals, Søren Østergaard, Erica Nishimura & Thomas Kjeldsen

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  1. Peter Kurtzhals
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  2. Søren Østergaard
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Correspondence to Peter Kurtzhals.

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Competing interests

All authors are employees and shareholders of Novo Nordisk A/S. T.K. is co-inventor of insulin analogues, which are described in the following patents: WO2009/115469, US Patent 9,035,020 B1 and WO2015/128403 A2. S.O. is co-inventor of peptide YY (PYY) analogues which are described in US Patent US2015/0152150 A1.

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Supplementary information

Supplementary Table 1: Studies reporting the half-life of drug compounds presented in the figure of Box 3.

Supplementary Video 1: The multiple roles of fatty acid derivatisation in the design of long-acting insulin analogues.

Using examples of different modified insulin molecules, this video highlights some principles that have been applied to the engineering of long-acting insulin analogues by fatty acid derivatisation. It specifically demonstrates the varied protraction mechanisms enabled for once-daily insulin detemir and insulin degludec as well as for once-weekly insulin icodec.

Glossary

Fatty acid derivatization

The chemical coupling of a fatty acid side chain onto a peptide or a protein.

Lipidation

Attachment of a fatty acid to a peptide or protein. Sometimes used as an alternative term for ‘fatty acid derivatization’ in drug discovery.

Protraction

Extending the half-life of a drug compound.

Backbone

The chain of amino acids composing the primary structure of a peptide or protein.

Linker

The chemical element connecting the fatty acid to the spacer or to the peptide backbone in a fatty acid-derivatized peptide or protein.

Spacer

The chemical element connecting the linker and the peptide backbone in a fatty acid-derivatized peptide or protein.

Fatty monoacid

A fatty acid in the form of a long alkyl chain (12–22 carbon atoms) with one carboxylate group at the distal end.

Fatty diacid

A fatty acid in the form of a long alkyl chain with two carboxylate groups, one at each end.

Analogues

Peptides or proteins that have been modified by amino acid substitution, backbone modification and/or derivatization.

Hexamer

Quaternary structure in which six molecules self-associate into a structural unit.

Heptamer

Quaternary structure in which seven molecules self-associate into a structural unit.

Hyperinsulinaemic, euglycaemic clamp

A method to estimate the glucose-lowering effect of an insulin at high insulin concentrations.

Liver preferential insulin

An insulin analogue that exerts more of its action on the liver compared with subcutaneously administered human insulin.

Self-immolative systems

Chemical structures that spontaneously undergo a degradation reaction to release the active drug substance.

RNAi

Sequence-specific suppression of gene expression using modified RNA oligonucleotides.

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Kurtzhals, P., Østergaard, S., Nishimura, E. et al. Derivatization with fatty acids in peptide and protein drug discovery. Nat Rev Drug Discov 22, 59–80 (2023). https://doi.org/10.1038/s41573-022-00529-w

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