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ACS Chemical Biology Jul 2023Disulfide bonds form covalent bonds between distal regions of peptides and proteins to dramatically impact their folding, stability, and oligomerization. Given the...
Disulfide bonds form covalent bonds between distal regions of peptides and proteins to dramatically impact their folding, stability, and oligomerization. Given the prevalence of disulfide bonds in many natural products, considerable effort has been invested in site-selective disulfide bond formation approaches to control the folding of chemically synthesized peptides and proteins. Here, we show that the careful choice of thiol oxidation conditions can lead to monomeric or dimeric species from fully deprotected linear bisthiol peptides. Starting from a p53-derived peptide, we found that oxidation under aqueous (nondenaturing) conditions produces antiparallel dimers with enhanced α-helical character, while oxidation under denaturing conditions promotes formation of a nonhelical intramolecular disulfide species. Examination across peptide variants suggests that intramolecular disulfide formation is robust across diverse peptide sequences, while dimerization is sensitive to both the α-helical folding of the linear peptide and aromatic residues at the dimerization interface. All disulfide species are more resistant to protease degradation than the linear peptide but are easily reduced to restore the initial bisthiol peptide. Both disulfide formation approaches are compatible with α-helix-stabilizing cross-linkers. These results provide an approach for using disulfide bonds to control peptide folding and oligomerization to better understand how folding influences interactions with diverse molecular targets.
Topics: Disulfides; Protein Folding; Dimerization; Proteins; Peptides; Oxidation-Reduction
PubMed: 37390465
DOI: 10.1021/acschembio.3c00268 -
Current Opinion in Structural Biology Aug 2016Short helical peptides combine characteristics of small molecules and large proteins and provide an exciting area of opportunity in protein design. A growing number of... (Review)
Review
Short helical peptides combine characteristics of small molecules and large proteins and provide an exciting area of opportunity in protein design. A growing number of studies report novel helical peptide inhibitors of protein-protein interactions. New techniques have been developed for peptide design and for chemically stabilizing peptides in a helical conformation, which frequently improves protease resistance and cell permeability. We summarize advances in peptide crosslinking chemistry and give examples of peptide design studies targeting coiled-coil transcription factors, Bcl-2 family proteins, MDM2/MDMX, and HIV gp41, among other targets.
Topics: Animals; Drug Design; Humans; Peptides; Protein Binding; Protein Conformation, alpha-Helical; Proteins
PubMed: 27123812
DOI: 10.1016/j.sbi.2016.04.001 -
Biomolecules Jan 2021Since the isolation and commercialization of insulin (a peptide composed of 51 amino acid residues) in the early 1920s, peptide drugs have reshaped the pharmaceutical...
Since the isolation and commercialization of insulin (a peptide composed of 51 amino acid residues) in the early 1920s, peptide drugs have reshaped the pharmaceutical industry [...].
Topics: Animals; Biotechnology; Fermentation; Genomics; Humans; Nanotechnology; Peptide Hydrolases; Peptides
PubMed: 33401441
DOI: 10.3390/biom11010052 -
Xenobiotica; the Fate of Foreign... Apr 2023Challenges within peptide and oligonucleotide ADME (absorption, distribution, metabolism and elimination) and scientific ideas on how to solve them were presented and... (Review)
Review
Challenges within peptide and oligonucleotide ADME (absorption, distribution, metabolism and elimination) and scientific ideas on how to solve them were presented and discussed at the DMDG (Drug Metabolism and Discussion Group) Peptide and Oligonucleotide ADME Workshop 2022 (2nd and 3rd of October 2022). This meeting report summarises the presentations and discussions from this workshop.The following topics were covered:Overview of the drug modality landscapeMetabolism & modellingAnalytical challengesDrug-drug interactions reports from industry working groupsRegulatory interactions.
Topics: Peptides; Drug Interactions; Metabolic Clearance Rate
PubMed: 37309582
DOI: 10.1080/00498254.2023.2223666 -
Trends in Biotechnology Feb 2017Peptidic biomaterials represent a particularly exciting topic in regenerative medicine. Peptidic scaffolds can be specifically designed for biomimetic customization for... (Review)
Review
Peptidic biomaterials represent a particularly exciting topic in regenerative medicine. Peptidic scaffolds can be specifically designed for biomimetic customization for targeted therapy. The field is at a pivotal point where preclinical research is being translated into clinics, so it is crucial to understand the theory and describe the status of this rapidly developing technology. In this review, we highlight major advantages and current limitations of self-assembling peptide-based biomaterials, and we discuss the most widely used classes of assembling peptides, describing recent and promising approaches in tissue engineering, drug delivery, and clinics. We also suggest design strategies and hurdles that still need to be overcome to fully exploit their therapeutic potential.
Topics: Biomimetic Materials; Extracellular Matrix; Nanocapsules; Peptides; Protein Binding; Tissue Engineering; Tissue Scaffolds
PubMed: 27717599
DOI: 10.1016/j.tibtech.2016.09.004 -
Methods in Molecular Biology (Clifton,... 2019Macrocyclic peptides are a unique class of molecules that display a relatively constrained peptidic backbone as compared to their linear counterparts leading to the... (Review)
Review
Macrocyclic peptides are a unique class of molecules that display a relatively constrained peptidic backbone as compared to their linear counterparts leading to the defined 3-D orientation of the constituent amino acids (pharmacophore). Although they are attractive candidates for lead discovery owing to the unique conformational features, their peptidic backbone is susceptible to proteolytic cleavage in various biological fluids that compromise their efficacy. In this chapter we review the various classical and contemporary chemical and biological approaches that have been utilized to combat the metabolic instability of macrocyclic peptides. We note that any chemical modification that helps in providing either local or global conformational rigidity to these macrocyclic peptides aids in improving their metabolic stability typically by slowing the cleavage kinetics by the proteases.
Topics: Administration, Oral; Conotoxins; Cyclization; Cyclotides; High-Throughput Screening Assays; Kinetics; Methylation; Molecular Conformation; Peptide Hormones; Peptides, Cyclic; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand
PubMed: 31134565
DOI: 10.1007/978-1-4939-9504-2_2 -
Food & Function Dec 2017Peptides have been demonstrated as potentially beneficial compounds against several life-style related diseases such as hypertension, hypercholesterolemia, and... (Review)
Review
Peptides have been demonstrated as potentially beneficial compounds against several life-style related diseases such as hypertension, hypercholesterolemia, and atherosclerosis, among others. However, limited research has been carried out on peptide absorption, resulting in a lack of understanding and control of this process. Therefore, this review discusses the recent insights gathered on in vitro and in vivo absorption of peptides across intestinal membranes, into blood circulation. Briefly, some di-/tripeptides permeate through intestinal membranes in their intact forms via peptide transporter systems, while others are vulnerable to protease degradation. Oligopeptides (>tetrapeptides) show a lower transport ability than di-/tripeptides, possibly due to the presence of paracellular tight junctions. The hydrophobicity of peptides (log P) does not seem to influence absorption, while peptide length and degradation of peptides (and peptide sequences) by intestinal proteases may be determinant factors of the absorption process.
Topics: Animals; Biological Transport; Humans; Intestinal Absorption; Intestinal Mucosa; Peptides
PubMed: 29139513
DOI: 10.1039/c7fo01185g -
Chemical Society Reviews Aug 2015Through their unique and specific interactions with various metal ions, naturally occurring proteins control structures and functions of many biological processes and... (Review)
Review
Through their unique and specific interactions with various metal ions, naturally occurring proteins control structures and functions of many biological processes and functions in organisms. Inspired by natural metallopeptides, chemists have developed artificial peptides which coordinate with metal ions through their functional groups either for introducing a special reactivity or for constructing nanostructures. However, the design of new coordination peptides requires a deep understanding of the structures, assembly properties, and dynamic behaviours of such peptides. This review briefly discusses strategies of peptide self-assembly induced by metal coordination to different natural and non-natural binding sites in the peptide. The structures and functions of the obtained aggregates are described as well. We also highlight some examples of a metal-induced peptide self-assembly with relevance to biotechnology applications.
Topics: Binding Sites; Biochemistry; Coordination Complexes; Metals; Peptides; Protein Binding
PubMed: 25952028
DOI: 10.1039/c5cs00234f -
Xenobiotica; the Fate of Foreign... Aug 2022Many peptide drugs such as insulin and glucagon-like peptide (GLP-1) analogues are successfully administered subcutaneously (SC). Following SC injection, peptides may... (Review)
Review
Many peptide drugs such as insulin and glucagon-like peptide (GLP-1) analogues are successfully administered subcutaneously (SC). Following SC injection, peptides may undergo catabolism in the SC compartment before entering systemic circulation, which could compromise their bioavailability and in turn affect their efficacy.This review will discuss how both technology and strategy have evolved over the past years to further elucidate peptide SC catabolism.Modern bioanalytical technologies (particularly liquid chromatography-high-resolution mass spectrometry) and bioinformatics platforms for data mining has prompted the development of , and tools for characterising peptide SC catabolism to rapidly address proteolytic liabilities and, ultimately, guide the design of peptides with improved SC bioavailability.More predictive models able to recapitulate the interplay between SC catabolism and other factors driving SC absorption are highly desirable to improve correlations.We envision the routine incorporation of and SC catabolism studies in ADME screening funnels to develop more effective peptide drugs for SC delivery.
Topics: Peptides; Insulin; Pharmaceutical Preparations; Biological Availability; Chromatography, Liquid; Injections, Subcutaneous
PubMed: 36039395
DOI: 10.1080/00498254.2022.2119180 -
Journal of Medicinal Chemistry Jan 2023The activation of G protein-coupled receptors (GPCRs) is triggered by ligand binding to their orthosteric sites, which induces ligand-specific conformational changes.... (Review)
Review
The activation of G protein-coupled receptors (GPCRs) is triggered by ligand binding to their orthosteric sites, which induces ligand-specific conformational changes. Agonists and antagonists bound to GPCR orthosteric sites provide detailed information on ligand-binding modes. Among these, peptide ligands play an instrumental role in GPCR pharmacology and have attracted increased attention as therapeutic drugs. The recent breakthrough in GPCR structural biology has resulted in the remarkable availability of peptide-bound GPCR complexes. Despite the several structural similarities shared by these receptors, they exhibit distinct features in terms of peptide recognition and receptor activation. From this perspective, we have summarized the current status of peptide-bound GPCR structural complexes, largely focusing on the interactions between the receptor and its peptide ligand at the orthosteric site. In-depth structural investigations have yielded valuable insights into the molecular mechanisms underlying peptide recognition. This study would contribute to the discovery of GPCR peptide drugs with improved therapeutic effects.
Topics: Protein Binding; Ligands; Receptors, G-Protein-Coupled; Peptides
PubMed: 36625741
DOI: 10.1021/acs.jmedchem.2c01309