A review of lipidation in the development of advanced protein and peptide therapeutics

Menacho‐Melgar, Romel; Decker, John S.; Hennigan, Jennifer N.; Lynch, Michael

doi:10.1016/j.jconrel.2018.12.032

Cited by 99 publications

(98 citation statements)

References 134 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In clinically approved peptide products, there are two major strategies to extending the duration of action; the first involves chemical conjugation or biosynthetic fusion of fatty acid, PEG, albumin [ 212 ], XTEN [ 213 ], elastin-like-polypeptide [ 214 ] or Fc region [ 215 ] to the peptide. While this chemical conjugation has shown promising clinical results via the SC route, it requires drug re-synthesis, which can lead to loss in higher order structure and unpredictable effects on potency [ 216 ]. A second approach relies on carrier mechanisms to deliver a fixed dosage of the drug in its original form over an extended period of time, without influencing the half-life of the therapeutic.…”

Section: Polypeptide Deliverymentioning

confidence: 99%

Injectables and Depots to Prolong Drug Action of Proteins and Peptides

et al. 2020

View full text Add to dashboard Cite

Proteins and peptides have emerged in recent years to treat a wide range of multifaceted diseases such as cancer, diabetes and inflammation. The emergence of polypeptides has yielded advancements in the fields of biopharmaceutical production and formulation. Polypeptides often display poor pharmacokinetics, limited permeability across biological barriers, suboptimal biodistribution, and some proclivity for immunogenicity. Frequent administration of polypeptides is generally required to maintain adequate therapeutic levels, which can limit efficacy and compliance while increasing adverse reactions. Many strategies to increase the duration of action of therapeutic polypeptides have been described with many clinical products having been developed. This review describes approaches to optimise polypeptide delivery organised by the commonly used routes of administration. Future innovations in formulation may hold the key to the continued successful development of proteins and peptides with optimal clinical properties.

show abstract

Section: Polypeptide Deliverymentioning

confidence: 99%

Injectables and Depots to Prolong Drug Action of Proteins and Peptides

et al. 2020

View full text Add to dashboard Cite

show abstract

“…[3,8] We expect this approach to be versatile enough to be combined with other known peptide stabilization methods (e.g. b-amino acid replacement, [7d] macrocyclization, [4] lipidation [27] )t of urther increase helical content, potency, and resistance to proteases.T he general principles that have been discussed here may thus facilitate lead peptide optimization and the design of more efficient and specific foldamer sequences as disruptors of PPIs or as receptor ligands.…”

Section: Forschungsartikelmentioning

confidence: 99%

Structural Basis for α‐Helix Mimicry and Inhibition of Protein–Protein Interactions with Oligourea Foldamers

et al. 2020

View full text Add to dashboard Cite

Efficient optimization of a peptide lead into a drug candidate frequently needs further transformation to augment properties such as bioavailability. Among the different options, foldamers, which are sequence‐based oligomers with precise folded conformation, have emerged as a promising technology. We introduce oligourea foldamers to reduce the peptide character of inhibitors of protein–protein interactions (PPI). However, the precise design of such mimics is currently limited by the lack of structural information on how these foldamers adapt to protein surfaces. We report a collection of X‐ray structures of peptide–oligourea hybrids in complex with ubiquitin ligase MDM2 and vitamin D receptor and show how such hybrid oligomers can be designed to bind with high affinity to protein targets. This work should enable the generation of more effective foldamer‐based disruptors of PPIs in the context of peptide lead optimization.

show abstract

“…5 For example, the half-life of several peptide drugs, including glucagon-like peptide-1 (GLP-1), growth hormone, calcitonin, and insulin, has been greatly increased via the conjugation of FAs to the corresponding therapeutic peptides. 6 Several therapeutic biodrugs, such as semaglutide and liraglutide, have been successfully developed via the conjugation of FAs to therapeutic peptides and all conjugates display improved efficiencies in vivo in clinical applications. 7 However, whether conjugation of a FA to PTH1-34 would extend the half-life of the peptide drug remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a Novel PTH1–34 Analog with Increased Human Serum Albumin Affinity

Ruan

Dong

et al. 2021

Pharmaceutical Fronts

View full text Add to dashboard Cite

Parathyroid hormone (PTH)1–34 is an effective peptide drug for osteoporosis therapy. However, the half-life of PTH1–34 in vivo is short, leading to the need for frequent injections of this drug during its treatment. To prolong the half-life of PTH1–34, a novel PTH1–34 analog was generated based on fatty acid generation, and its synthesis process included recombinant protein expression, side-chain modification, and peptide decoration. The PTH1–34 variant was expressed in Escherichia coli, with a single Lys (position 27) retained as a modification site. The side chain, –AEEA-γGlu-C18 diacid, was synthesized using 2-chlorotrityl chloride resin as a solid support, and then was conjugated to the PTH1-34 variant to form PTH-Lys27-AGC. Reversed-phase chromatography confirmed a high final purity (>98%) of the target compound; in vitro bioactivity tests showed that PTH-1 receptor potency of PTH-Lys27-AGC was comparable to that of the native PTH1–34. A competitive human serum albumin binding test demonstrated a high albumin affinity of PTH-Lys27-AGC in comparison to PTH1–34. In summary, we developed a novel PTH1–34 analog, PTH-Lys27-AGC, which may be a long-acting agent for osteoporosis treatment in the future.

show abstract

A review of lipidation in the development of advanced protein and peptide therapeutics

Cited by 99 publications

References 134 publications

Injectables and Depots to Prolong Drug Action of Proteins and Peptides

Injectables and Depots to Prolong Drug Action of Proteins and Peptides

Structural Basis for α‐Helix Mimicry and Inhibition of Protein–Protein Interactions with Oligourea Foldamers

Synthesis of a Novel PTH1–34 Analog with Increased Human Serum Albumin Affinity

Contact Info

Product

Resources

About