Peptide Lipidation

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What is Peptide Lipidation?

Lipidation is a post-translational modification of peptides and proteins. Some nonribosomally synthesized bacterial antibiotics and ghrelin are naturally-occurring lipidated peptides. Peptide lipidation is a process in which a peptide molecule is attached to a lipid molecule. This modification can occur naturally in living organisms or can be performed artificially in the laboratory.

Peptide drugs offer many desirable drug properties such as potent bioactivity, high receptor binding affinity and specificity, and relatively low toxicity. However, most peptides are quickly degraded in serum and exhibit rapid clearance in vivo. Many strategies have been employed in an attempt to overcome these apparent disadvantages including lipidation, glycosylation, cyclization, backbone modification, unnatural or D-amino acid conjugation and PEGylation. Among these chemical modification methods, lipidation has proven to be one of the most robust strategies for the generation of new therapeutic peptide.

Lipidized Peptide

Four lipidized peptide drugs are currently approved for use in humans: two long-acting anti-diabetics human glucagon-like peptide-1 (GLP-1) analogue liraglutide and insulin detemir, and two antibiotics daptomycin and polymixin B. A number of lipidated peptides, lipoproteins and lipidated peptide vaccines are at different phases of clinical trials. As indicated in Table 1, lipidation was extensively exploited in the drug developments.

Structures of ghrelin, GLP-1 (liraglutide) and insulin detemirStructures of ghrelin, GLP-1 (liraglutide) and insulin detemir (Zhang L, et,al. 2012)

Table 1

Fatty acidEnkephalin, Galanin, GIP, GLP-1 (liraglutide), hPP, IGF1R JM inhibitor, Insulin; Leuteinizing hormone releasing hormone (LHRH), NPW, NPY, NT, RC-160, STAT3, Tetragastrin, Thyrotropin releasing hormone (TRH)
Amino fatty acidConotoxin SIIIA, Ghrelin, Liraglutide, Met-Enkephalin, TAN-1511A, Tenecin-1
Acidic fatty acid (dicarboxylic acid)Growth hormone-releasing hormone antagonists (GHRH)
Halo-fatty acidGhrelin
Lipoamino acidCore peptide, Thymopentin TP5, Peptide A2, Polycationic lipophilic core dendron excipient
Alkyl ether (O-, S-)Angiotensin
Alkyl amineCompound 3
CholesterolC34, Insulin

Types of Lipidation

Lipidation can be classified into three types based on lipid bond formation methods with peptide chain or side chains: amidation, esterification (S- or O-) and S-bond (ether or disulfide) formation. Amidation and O-esterification are strong and irreversible covalent bonds, whereas S-esterification and disulfide bond formation are weak and reversible covalent bonds.

Application of Peptide Lipidation

  • Peptide lipidation can modulate the physicochemical and pharmacological properties of bioactive peptides generating therapeutically useful targets.
  • Lipidation provides a simple way to increased peptide lipophilicity.
  • Lipidation alters absorption, distribution, metabolism, and excretion (ADME) properties and therefore is an attractive tool to convert peptides into drug candidates
  • Lipidation can change the secondary structures of peptides through the hydrophobic interactions of the fatty acid chain with the peptide backbone or side chains
  • Lipidation increases peptides' plasma stability and decreases peptides' kidney clearance.
  • Lipidated peptides can form stable oligomers, self-assembling structures (such as micelles, tubules, vesicles, mono- or bilayers, nanofibers) and aggregates.
  • Lipidation affects peptide-membrane interactions. The interactions may have tremendous effects on the physical properties of membranes, such as the fluidity, free volume, intrinsic curvature and morphologies of the membrane.
  • Lipidation on a noncritical terminus is an important strategy to maintain peptides' receptor binding ability.
  • Peptide lipidation is an effective strategy to increase the drugable potential of bioactive peptides.
  • Peptide lipidation dramatically increase enzymatic stability, receptor selectivity and potency, bioavailability and drug delivery potential

Our Peptide Lipidation Services


  1. Kowalczyk R, Harris P W R, Williams G M, et al. Peptide lipidation–a synthetic strategy to afford peptide based therapeutics[J]. Peptides and peptide-based biomaterials and their biomedical applications, 2017: 185-227.
  2. Zhang L, Bulaj G. Converting peptides into drug leads by lipidation[J]. Current medicinal chemistry, 2012, 19(11): 1602-1618.
* Please kindly note that our products and services can only be used to support research purposes (Not for clinical use).
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