Peptide lipidation stabilizes structure to enhance biological function.

Medicines that decrease body weight and restore nutrient tolerance could improve human diabetes and obesity treatment outcomes. We developed lipid-acylated glucagon analogs that are co-agonists for the glucagon and glucagon-like peptide 1 receptors, and stimulate weight loss and plasma glucose lowering in pre-diabetic obese mice. Our studies identified lipid acylation (lipidation) can increase and balance in vitro potencies of select glucagon analogs for the two aforementioned receptors in a lipidation site-dependent manner. A general capacity for lipidation to enhance the secondary structure of glucagon analogs was recognized, and the energetics of this effect quantified. The molecular structure of a lipid-acylated glucagon analog in water was also characterized. These results support that lipidation can modify biological activity through thermodynamically-favorable intramolecular interactions which stabilize structure. This establishes use of lipidation to achieve specific pharmacology and implicates similar endogenous post-translational modifications as physiological tools capable of refining biological action in means previously underappreciated.

• Publication year

  2013

• Venue

  Molecular Metabolism

• Publication date

  2013-11-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.molmet.2013.08.008PMID 24327962PMCID PMC3854995
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide.

  2012cited by this paper
• Optimization of co‐agonism at GLP‐1 and glucagon receptors to safely maximize weight reduction in DIO‐rodents

  2012cited by this paper
• Functional association of the N‐terminal residues with the central region in glucagon‐related peptides

  2011cited by this paper
• Protein palmitoylation and subcellular trafficking.

  2011cited by this paper
• Dynamic structure of membrane-anchored Arf•GTP

  2010cited by this paper
• Interplay of Palmitoylation and Phosphorylation in the Trafficking and Localization of Phosphodiesterase 10A: Implications for the Treatment of Schizophrenia

  2010cited by this paper
• A new glucagon and GLP-1 co-agonist eliminates obesity in rodents.

  2009cited by this paper
• Molecular, pharmacological and clinical aspects of liraglutide, a once-daily human GLP-1 analogue.

  2009cited by this paper
• Glucagon-Like Peptide 1/Glucagon Receptor Dual Agonism Reverses Obesity in Mice

  2009influential reference
• Stabilization of conformationally dynamic helices by covalently attached acyl chains

  2009cited by this paper
• Solid phase peptide synthesis utilizing 9-fluorenylmethoxycarbonyl amino acids.

  2009cited by this paper
• Regulation of AMPA receptor extrasynaptic insertion by 4.1N, phosphorylation and palmitoylation

  2009cited by this paper
• Large-scale profiling of protein palmitoylation in mammalian cells

  2009cited by this paper
• Passing the baton in class B GPCRs: peptide hormone activation via helix induction?

  2009cited by this paper
• Farnesylation of the SNARE protein Ykt6 increases its stability and helical folding.

  2008cited by this paper
• Neural Palmitoyl-Proteomics Reveals Dynamic Synaptic Palmitoylation

  2008cited by this paper
• Site-specific Effects of Peptide Lipidation on β-Amyloid Aggregation and Cytotoxicity*

  2007cited by this paper
• Structure-activity and protraction relationship of long-acting glucagon-like peptide-1 derivatives: importance of fatty acid length, polarity, and bulkiness.

  2007cited by this paper
• Using circular dichroism spectra to estimate protein secondary structure

  2007cited by this paper
• BioMagResBank

  2007cited by this paper
• The bioactive conformation of glucose‐dependent insulinotropic polypeptide by NMR and CD spectroscopy

  2007cited by this paper
• Using circular dichroism collected as a function of temperature to determine the thermodynamics of protein unfolding and binding interactions

  2006influential reference
• The Mechanism of Protraction of Insulin Detemir, a Long-Acting, Acylated Analog of Human Insulin

  2004cited by this paper
• Evaluation of a quantitative magnetic resonance method for mouse whole body composition analysis.

  2004cited by this paper
• The Xplor-NIH NMR molecular structure determination package.

  2003influential reference
• Effect of phosphorylation on α-helix stability as a function of position

  2002cited by this paper
• Effect of phosphorylation on alpha-helix stability as a function of position.

  2002cited by this paper
• Trifluoroethanol may form a solvent matrix for assisted hydrophobic interactions between peptide side chains.

  2000cited by this paper
• Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration.

  2000influential reference
• Positively Charged Residues at Positions 12, 17, and 18 of Glucagon Ensure Maximum Biological Potency*

  1998cited by this paper
• Principles of physical biochemistry

  1998cited by this paper
• Phosphorylation destabilizes alpha-helices.

  1997cited by this paper
• Phosphorylation destabilizes α-helices

  1997cited by this paper
• Concept and early development of solid-phase peptide synthesis.

  1997cited by this paper
• Palmitoylated Cysteine 341 Modulates Phosphorylation of the β2-Adrenergic Receptor by the cAMP-dependent Protein Kinase*

  1996cited by this paper
• Secondary structure and biophysical activity of synthetic analogues of the pulmonary surfactant polypeptide SP-C.

  1995cited by this paper
• NMRPipe: A multidimensional spectral processing system based on UNIX pipes

  1995cited by this paper
• Multiple-site replacement analogs of glucagon. A molecular basis for antagonist design.

  1994cited by this paper
• Structure of glucagon-like peptide (7-36) amide in a dodecylphosphocholine micelle as determined by 2D NMR.

  1994cited by this paper
• Structure-activity studies of glucagon-like peptide-1.

  1994cited by this paper
• NMR of proteins and nucleic acids

  1988cited by this paper
• Importance of the 10-13 region of glucagon for its receptor interactions and activation of adenylate cyclase.

  1986cited by this paper
• Conformation of glucagon in a lipid-water interphase by 1H nuclear magnetic resonance.

  1983cited by this paper

• Design and Biosynthesis of Ornithine 8-Containing Semaglutide Variants with a Click Chemistry-Modifiable Position 26

  2025cites this paper
• Prolonging parathyroid hormone analog action in vitro and in vivo through peptide lipidation

  2025influential citation
• Design of a novel long-acting insulin analogs by acetylation modification and compared with insulin Icodec

  2025cites this paper
• PACAP sequence modifications modulate the peptide antimicrobial activity against bacterial pathogens affecting aquaculture.

  2024cites this paper
• Peripheral administration of lipidized NPAF and NPFF analogs does not influence central food intake regulation but induces anxiety-like behavior.

  2024cites this paper
• Insulin fibrillation under physicochemical parameters of bioprocessing and intervention by peptides and surface-active agents

  2024cites this paper
• Fatty Acid Derivatization and Cyclization of the Immunomodulatory Peptide RP-182 Targeting CD206high Macrophages Improve Antitumor Activity

  2024cites this paper
• Peptides for therapeutic applications – challenges and chances

  2024cites this paper
• Machine learning designs new GCGR/GLP-1R dual agonists with enhanced biological potency

  2024cites this paper
• Evolution of Peptide Drug Biopharmaceutics

  2023cites this paper
• Evolution of Peptide Biopharmaceuticals

  2023cites this paper
• Lipidization as a tool toward peptide therapeutics

  2023cites this paper
• A Spectroscopic and Molecular Dynamics Study on the Aggregation Properties of a Lipopeptide Analogue of Liraglutide, a Therapeutic Peptide against Diabetes Type 2

  2023cites this paper
• Emerging roles of oxyntomodulin-based glucagon-like peptide-1/glucagon co-agonist analogs in diabetes and obesity.

  2023cites this paper
• Antimicrobial Peptides Controlling Resistant Bacteria in Animal Production

  2022cites this paper
• Artificial peptides to induce membrane denaturation and disruption and modulate membrane composition and fusion

  2022cites this paper
• Design, structure of amphiphilic peptide and its application from single molecule to nanoparticle

  2022cites this paper
• Antimicrobial Activity of Silver Nanoparticles Loaded Biomimetic Isomeric Short Lipopeptide Nanostructures

  2022cites this paper
• Novel Therapies for Cardiometabolic Disease: Recent Findings in Studies with Hormone Peptide-Derived G Protein Coupled Receptor Agonists

  2022cites this paper
• Therapeutic Peptides: Unravelling Conformational Dynamics by Systematic Application of Biophysical Techniques.

  2022cites this paper
• Derivatization with fatty acids in peptide and protein drug discovery

  2022cites this paper
• Discovery of MK-1462: GLP-1 and Glucagon Receptor Dual Agonist for the Treatment of Obesity and Diabetes.

  2022cites this paper
• Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice

  2022cites this paper
• Development of Peptide Biopharmaceuticals in Russia

  2022cites this paper
• Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist

  2021cites this paper
• Photo-induced radical thiol-ene chemistry: a versatile toolbox for peptide-based drug design.

  2021cites this paper
• Vasoactive Intestinal Peptide Amphiphile Micelle Chemical Structure and Hydrophobic Domain Influence Immunomodulatory Potentiation

  2021cites this paper
• Peptides Derived from Vascular Endothelial Growth Factor B Show Potent Binding to Neuropilin‐1

  2021cites this paper
• Antimicrobial peptides used as growth promoters in livestock production

  2021cites this paper
• Discovery of a Long-Acting Parathyroid Hormone 1-34 Analogue to Treat Hypoparathyroidism.

  2021cites this paper
• A Facile Procedure for One-Pot Stable Conjugation of Two Proglucagon Cysteine-Containing Peptide Analogs

  2021cites this paper
• Developing GLP-1 Conjugated Self-Assembling Nanofibers Using Copper-Catalyzed Alkyne-Azide Cycloaddition and Evaluation of Their Biological Activity.

  2021cites this paper
• High-Throughput Screening for Colloidal Stability of Peptide Formulations Using Dynamic and Static Light Scattering.

  2021cites this paper
• PepTherDia: database and structural composition analysis of approved peptide therapeutics and diagnostics.

  2021cites this paper
• Identification of Potent and Long-Acting Single-Chain Peptide Mimetics of Human Relaxin-2 for Cardiovascular Diseases.

  2021cites this paper
• Modulation of Antimicrobial Peptide Conformation and Aggregation by Terminal Lipidation and Surfactants.

  2020cites this paper
• Self-assembly of exendin-4 derived dual peptide agonists is mediated by acylation and correlated to length of conjugated fatty acyl chain.

  2020cites this paper
• Prebiotic Peptides: Molecular Hubs in the Origin of Life.

  2020cites this paper
• Design of novel Xenopus GLP-1-based dual glucagon-like peptide 1 (GLP-1)/glucagon receptor agonists.

  2020cites this paper
• Novel formulation of antimicrobial peptides enhances antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA)

  2020cites this paper
• Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer's and Parkinson's disease therapeutics.

  2020cites this paper
• Glycopeptide Drugs: A Pharmacological Dimension Between "Small Molecules" and "Biologics".

  2020cites this paper
• Transition metal ions induced secondary structural transformation in a hydrophobized short peptide amphiphile

  2020cites this paper
• The Structural Refinement of Glucagon for Therapeutic Use.

  2019cites this paper
• Hitting Undruggable Targets: Viewing Stabilized Peptide Development through the Lens of Quantitative Systems Pharmacology.

  2019cites this paper
• Self-Assembly of Lipopeptides Containing Short Peptide Fragments Derived from the Gastrointestinal Hormone PYY3–36: From Micelles to Amyloid Fibrils

  2019cites this paper
• Design of Stapled Oxyntomodulin Analogs Containing Functionalized Biphenyl Cross-Linkers.

  2019cites this paper
• Genetically Encoded Cholesterol-Modified Polypeptides.

  2019cites this paper
• Design, Synthesis, and Evaluation of Lipopeptide Conjugates of Mercaptoundecahydrododecaborate for Boron Neutron Capture Therapy

  2019cites this paper
• NMR Assisted Antimicrobial Peptide Designing: Structure Based Modifications and Functional Correlation of A Designed Peptide VG16KRKP.

  2019cites this paper
• Glutamic Acid-Based Dendritic Peptides for Scaffold-free Cartilage Tissue Engineering.

  2019cites this paper
• Application of N-Dodecyl l-Peptide to Enhance Serum Stability while Maintaining Inhibitory Effects on Myometrial Contractions Ex Vivo

  2019cites this paper
• Selection and progression of unimolecular agonists at the GIP, GLP-1, and glucagon receptors as drug candidates.

  2019cites this paper
• Effect of Heat Treatment on the Antioxidant and Antihypertensive Activity as Well as in vitro Digestion Stability of Mackerel (Scomber scombrus) Protein Hydrolysates

  2019cites this paper
• Solid-Phase Thiol-Ene Lipidation of Peptides for the Synthesis of a Potent CGRP Receptor Antagonist.

  2018cites this paper
• Targeting the Incretin/Glucagon System With Triagonists to Treat Diabetes

  2018cites this paper
• Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists Specifically Optimized for Multidose Formulations.

  2018cites this paper
• Impact of processing on the chemistry and functionality of food proteins

  2018cites this paper
• Structure-Stability-Function Mechanistic Links in the Anti-Measles Virus Action of Tocopherol-Derivatized Peptide Nanoparticles.

  2018cites this paper
• Peptide chemistry toolbox - Transforming natural peptides into peptide therapeutics.

  2018cites this paper
• Stapled, Long-Acting Glucagon-like Peptide 2 Analog with Efficacy in Dextran Sodium Sulfate Induced Mouse Colitis Models.

  2018cites this paper
• Peptides for biopharmaceutical applications

  2018cites this paper
• Max Bergmann award lecture:Macromolecular medicinal chemistry as applied to metabolic diseases

  2018cites this paper
• Protein and Peptide Biopharmaceuticals: An Overview.

  2017cites this paper
• Molecular Imaging Agent Design for Quantifying Beta Cell Mass in Type 1 Diabetes

  2017cites this paper
• Late-stage lipidation of fully elaborated tryptophan-containing peptides for improved pharmacokinetics

  2017cites this paper
• Optimization of peptide-based polyagonists for treatment of diabetes and obesity.

  2017cites this paper
• Design of Novel Exendin-Based Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists.

  2017cites this paper
• Factors affecting the physical stability (aggregation) of peptide therapeutics

  2017cites this paper
• Lipopeptides as therapeutics: applications and in vivo quantitative analysis.

  2017cites this paper
• Peptide Lipidation – A Synthetic Strategy to Afford Peptide Based Therapeutics

  2017influential citation
• Effect of palmitoylated prolactin-releasing peptide on food intake and neural activation after different routes of peripheral administration in rats.

  2016cites this paper
• The molecular basis for the prolonged blood circulation of lipidated incretin peptides: Peptide oligomerization or binding to serum albumin?

  2016influential citation
• Acylation of Therapeutic Peptides: Interaction with Lipid Membranes and its Implications in Oral Delivery

  2016cites this paper
• Innovative chemical synthesis and conformational hints on the lipopeptide liraglutide

  2016cites this paper
• Broad-spectrum antiviral peptides against respiratory viruses

  2016cites this paper
• Adrenomedullin 2.0: Adjusting Key Levers for Metabolic Stability.

  2016cites this paper
• Engineering a long-acting, potent GLP-1 analog for microstructure-based transdermal delivery

  2016cites this paper
• A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity.

  2016cites this paper
• Design of Potent and Proteolytically Stable Oxyntomodulin Analogs.

  2016cites this paper
• Lipidation Effect on Surface Adsorption and Associated Fibrillation of the Model Protein Insulin.

  2016cites this paper
• Antimicrobial peptides: an alternative for innovative medicines?

  2015cites this paper
• Transformation of oligomers of lipidated peptide induced by change in pH.

  2015cites this paper
• Small cyclic agonists of iron regulatory hormone hepcidin.

  2015cites this paper
• A structure-function study of PACAP using conformationally restricted analogs: Identification of PAC1 receptor-selective PACAP agonists.

  2015cites this paper
• High metabolic in vivo stability and bioavailability of a palmitoylated ghrelin receptor ligand assessed by mass spectrometry.

  2015cites this paper
• Isolation of Positive Modulator of Glucagon-like Peptide-1 Signaling from Trigonella foenum-graecum (Fenugreek) Seed*

  2015cites this paper
• Position and Length of Fatty Acids Strongly Affect Receptor Selectivity Pattern of Human Pancreatic Polypeptide Analogues

  2014cites this paper
• Comparison of stability, cellular, glucose-lowering and appetite supressing effects of oxyntomodulin analogues modified at the N-terminus.

  2014cites this paper
• A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents

  2014cites this paper