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Bioconjugate Chemistry Jul 2018Therapeutic compounds with narrow therapeutic windows and significant systemic side effects benefit from targeted drug delivery strategies. Peptide-protein interactions... (Review)
Review
Therapeutic compounds with narrow therapeutic windows and significant systemic side effects benefit from targeted drug delivery strategies. Peptide-protein interactions are often exploited for targeting, with phage display a primary method to identify high-affinity peptide ligands that bind cell surface and matrix bound receptors preferentially expressed in target tissues. After isolating and sequencing high-binding phages, peptides are easily synthesized and chemically modified for incorporation into drug delivery systems, including peptide-drug conjugates, polymers, and nanoparticles. This review describes the phage display methodology to identify targeting peptide sequences, strategies to functionalize drug carriers with phage-derived peptides, specific examples of drug carriers with in vivo translation, and limitations and future applications of phage display to drug delivery.
Topics: Cell Surface Display Techniques; Drug Carriers; Drug Delivery Systems; Humans; Molecular Targeted Therapy; Peptides
PubMed: 29889510
DOI: 10.1021/acs.bioconjchem.8b00285 -
Chimia Jun 2021Heteronuclear NMR in combination with isotope labelling is used to study folding of polypeptides induced by metals in the case of metallothioneins, binding of the...
Heteronuclear NMR in combination with isotope labelling is used to study folding of polypeptides induced by metals in the case of metallothioneins, binding of the peptidic allosteric modulator ρ-TIA to the human G-protein coupled α adrenergic receptor, the development of therapeutic drugs that interfere with the biosynthesis of the outer membrane of Gram-negative bacteria, and a system in which protein assembly is induced upon peptide addition. NMR in these cases is used to derive precise structural data and to study the dynamics.
Topics: Humans; Peptides; Receptors, Adrenergic, alpha-1
PubMed: 34233813
DOI: 10.2533/chimia.2021.505 -
Mts1 (S100A4) and Its Peptide Demonstrate Cytotoxic Activity in Complex with Tag7 (PGLYRP1) Peptide.International Journal of Molecular... Jun 2024Receptors of cytokines are major regulators of the immune response. In this work, we have discovered two new ligands that can activate the TNFR1 (tumor necrosis factor...
Receptors of cytokines are major regulators of the immune response. In this work, we have discovered two new ligands that can activate the TNFR1 (tumor necrosis factor receptor 1) receptor. Earlier, we found that the peptide of the Tag (PGLYRP1) protein designated 17.1 can interact with the TNFR1 receptor. Here, we have found that the Mts1 (S100A4) protein interacts with this peptide with a high affinity (K = 1.28 × 10 M), and that this complex is cytotoxic to cancer cells that have the TNFR1 receptor on their surface. This complex induces both apoptosis and necroptosis in cancer cells with the involvement of mitochondria and lysosomes in cell death signal transduction. Moreover, we have succeeded in locating the Mts1 fragment that is responsible for protein-peptide interaction, which highly specifically interacts with the Tag7 protein (K = 2.96 nM). The isolated Mts1 peptide M7 also forms a complex with 17.1, and this peptide-peptide complex also induces the TNFR1 receptor-dependent cell death. Molecular docking and molecular dynamics experiments show the amino acids involved in peptide binding and that may be used for peptidomimetics' development. Thus, two new cytotoxic complexes were created that were able to induce the death of tumor cells via the TNFR1 receptor. These results may be used in therapy for both cancer and autoimmune diseases.
Topics: Humans; Receptors, Tumor Necrosis Factor, Type I; Apoptosis; Protein Binding; Molecular Docking Simulation; Cell Line, Tumor; Peptides; Molecular Dynamics Simulation; Signal Transduction; Necroptosis; Oligopeptides; Cytokines
PubMed: 38928339
DOI: 10.3390/ijms25126633 -
ACS Chemical Biology Jan 2018Diabetes is a leading cause of death worldwide and results in over 3 million annual deaths. While insulin manages the disease well, many patients fail to comply with...
Diabetes is a leading cause of death worldwide and results in over 3 million annual deaths. While insulin manages the disease well, many patients fail to comply with injection schedules, and despite significant investment, a more convenient oral formulation of insulin is still unavailable. Studies suggest that glycosylation may stabilize peptides for oral delivery, but the demanding production of homogeneously glycosylated peptides has hampered transition into the clinic. We report here the first total synthesis of homogeneously glycosylated insulin. After characterizing a series of insulin glycoforms with systematically varied O-glycosylation sites and structures, we demonstrate that O-mannosylation of insulin B-chain Thr27 reduces the peptide's susceptibility to proteases and self-association, both critical properties for oral dosing, while maintaining full activity. This work illustrates the promise of glycosylation as a general mechanism for regulating peptide activity and expanding its therapeutic use.
Topics: Animals; Cell Line; Drug Design; Glucose Transporter Type 4; Humans; Insulin; Mice; Protein Engineering; Structure-Activity Relationship; Threonine
PubMed: 29090903
DOI: 10.1021/acschembio.7b00794 -
International Journal of Molecular... May 2015Fabrication of self-assembled nanostructures is one of the important aspects in nanoscience and nanotechnology. The study of self-assembled soft materials remains an... (Review)
Review
Fabrication of self-assembled nanostructures is one of the important aspects in nanoscience and nanotechnology. The study of self-assembled soft materials remains an area of interest due to their potential applications in biomedicine. The versatile properties of soft materials can be tuned using a bottom up approach of small molecules. Peptide based self-assembly has significant impact in biology because of its unique features such as biocompatibility, straight peptide chain and the presence of different side chain functionality. These unique features explore peptides in various self-assembly process. In this review, we briefly introduce chemical reaction-mediated peptide self-assembly. Herein, we have emphasised enzymes, native chemical ligation and photochemical reactions in the exploration of peptide self-assembly.
Topics: Biocatalysis; Chemical Phenomena; Hydrolysis; Light; Models, Molecular; Peptides
PubMed: 25984603
DOI: 10.3390/ijms160510797 -
British Journal of Pharmacology Oct 2017The RFamide neuropeptide 26RFa was first isolated from the brain of the European green frog on the basis of cross-reactivity with antibodies raised against bovine... (Review)
Review
The RFamide neuropeptide 26RFa was first isolated from the brain of the European green frog on the basis of cross-reactivity with antibodies raised against bovine neuropeptide FF (NPFF). 26RFa and its N-terminally extended form glutamine RF-amide peptide (QRFP) have been identified as cognate ligands of the former orphan receptor GPR103, now renamed glutamine RF-amide peptide receptor (QRFP receptor). The 26RFa/QRFP precursor has been characterized in various mammalian and non-mammalian species. In the brain of mammals, including humans, 26RFa/QRFP mRNA is almost exclusively expressed in hypothalamic nuclei. The 26RFa/QRFP transcript is also present in various organs especially in endocrine glands. While humans express only one QRFP receptor, two isoforms are present in rodents. The QRFP receptor genes are widely expressed in the CNS and in peripheral tissues, notably in bone, heart, kidney, pancreas and testis. Structure-activity relationship studies have led to the identification of low MW peptidergic agonists and antagonists of QRFP receptor. Concurrently, several selective non-peptidic antagonists have been designed from high-throughput screening hit optimization. Consistent with the widespread distribution of QRFP receptor mRNA and 26RFa binding sites, 26RFa/QRFP exerts a large range of biological activities, notably in the control of energy homeostasis, bone formation and nociception that are mediated by QRFP receptor or NPFF2. The present report reviews the current knowledge concerning the 26RFa/QRFP-QRFP receptor system and discusses the potential use of selective QRFP receptor ligands for therapeutic applications.
Topics: Animals; Humans; Intercellular Signaling Peptides and Proteins; Neuropeptides; Peptides; Receptors, Neuropeptide
PubMed: 28613414
DOI: 10.1111/bph.13907 -
International Journal of Molecular... Feb 2023Synthetic antimicrobial and antibiofilm peptide (SAAP-148) commits significant antimicrobial activities against antimicrobial resistant (AMR) planktonic bacteria and...
Synthetic antimicrobial and antibiofilm peptide (SAAP-148) commits significant antimicrobial activities against antimicrobial resistant (AMR) planktonic bacteria and biofilms. However, SAAP-148 is limited by its low selectivity index, i.e., ratio between cytotoxicity and antimicrobial activity, as well as its bioavailability at infection sites. We hypothesized that formulation of SAAP-148 in PLGA nanoparticles (SAAP-148 NPs) improves the selectivity index due to the sustained local release of the peptide. The aim of this study was to investigate the physical and functional characteristics of SAAP-148 NPs and to compare the selectivity index of the formulated peptide with that of the peptide in solution. SAAP-148 NPs displayed favorable physiochemical properties [size = 94.1 ± 23 nm, polydispersity index (PDI) = 0.08 ± 0.1, surface charge = 1.65 ± 0.1 mV, and encapsulation efficiency (EE) = 86.7 ± 0.3%] and sustained release of peptide for up to 21 days in PBS at 37 °C. The antibacterial and cytotoxicity studies showed that the selectivity index for SAAP-148 NPs was drastically increased, by 10-fold, regarding AMR and 20-fold regarding AMR after 4 h. Interestingly, the antibiofilm activity of SAAP-148 NPs against AMR and gradually increased overtime, suggesting a dose-effect relationship based on the peptide's in vitro release profile. Using 3D human skin equivalents (HSEs), dual drug SAAP-148 NPs and the novel antibiotic halicin NPs provided a stronger antibacterial response against planktonic and cell-associated bacteria than SAAP-148 NPs but not halicin NPs after 24 h. Confocal laser scanning microscopy revealed the presence of SAAP-148 NPs on the top layers of the skin models in close proximity to AMR at 24 h. Overall, SAAP-148 NPs present a promising yet challenging approach for further development as treatment against bacterial infections.
Topics: Humans; Staphylococcus aureus; Antimicrobial Peptides; Anti-Bacterial Agents; Polylactic Acid-Polyglycolic Acid Copolymer; Anti-Infective Agents; Peptides; Bacteria; Nanoparticles; Biofilms
PubMed: 36769188
DOI: 10.3390/ijms24032867 -
Drug Discovery Today May 2023Cell migration is a key physiological process in the development and homeostasis of multicellular organisms; errors in this complex system can trigger the development of... (Review)
Review
Cell migration is a key physiological process in the development and homeostasis of multicellular organisms; errors in this complex system can trigger the development of cancer or inflammatory disorders. Therefore, modulating cell migration provides opportunities for drug discovery. Peptides are gaining importance on the global therapeutics market, given their unique properties compared with established small-molecule drugs or biologics. In this review, we identified over 470 peptides modulating cell migration and analyzed their characteristics. Over 95% of these peptides are in the discovery or preclinical stage, because the transition of peptide hits into drug leads often results in a bottleneck in the development process. We summarize chemical strategies in (pre-)clinical development to enhance drug-like properties of bioactive peptides.
Topics: Humans; Peptides; Neoplasms; Cell Movement
PubMed: 36921670
DOI: 10.1016/j.drudis.2023.103554 -
Biochimica Et Biophysica Acta.... Feb 2022Fluorescence spectroscopy is used to characterize the partition of three second-generation D,L-α-cyclic peptides to two lipid model membranes. The peptides have proven...
Fluorescence spectroscopy is used to characterize the partition of three second-generation D,L-α-cyclic peptides to two lipid model membranes. The peptides have proven antimicrobial activity, particularly against Gram positive bacteria, and the model membranes are formed of either with 1,2-dimyristoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DMPG) or its mixture with 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), at a molar ratio of (1:1). The peptide's intrinsic fluorescence was used in the Steady State and/or Time Resolved Fluorescence Spectroscopy experiments, showing that the peptides bind to the membranes, and the extent of their partition is thereof quantified. The peptide-induced membrane leakage was followed using an encapsulated fluorescent dye. Overall, the partition is mainly driven by electrostatics, but also involves hydrophobic interactions. The introduction of a hydrocarbon tail in one of the residues of the parent peptide, CPR, adjacent to the tryptophan (Trp) residue, significantly improves the partition of the modified peptides, CPRT10 and CPRT14, to both membrane systems. Further, we show that the length of the tail is the main distinguishing factor for the extension of the partition process. The parent peptide induces very limited leakage, at odds with the peptides with tail, that promote fast leakage, increasing in most cases with peptide concentration, and being almost complete for the highest peptide concentration and negatively charged membranes. Overall, the results help the unravelling of the antimicrobial action of these peptides and are well in line with their proven high antimicrobial activity.
Topics: Anti-Bacterial Agents; Antimicrobial Peptides; Gram-Positive Bacteria; Humans; Hydrophobic and Hydrophilic Interactions; Membrane Lipids; Membranes; Peptides, Cyclic; Phosphatidylethanolamines; Phosphatidylglycerols; Spectrometry, Fluorescence
PubMed: 34506796
DOI: 10.1016/j.bbamem.2021.183729 -
Scientific Reports Jun 2021Peptide glycation is an important, yet poorly understood reaction not only found in food but also in biological systems. The enormous heterogeneity of peptides and the...
Peptide glycation is an important, yet poorly understood reaction not only found in food but also in biological systems. The enormous heterogeneity of peptides and the complexity of glycation reactions impeded large-scale analysis of peptide derived glycation products and to understand both the contributing factors and how this affects the biological activity of peptides. Analyzing time-resolved Amadori product formation, we here explored site-specific glycation for 264 peptides. Intensity profiling together with in-depth computational sequence deconvolution resolved differences in peptide glycation based on microheterogeneity and revealed particularly reactive peptide collectives. These peptides feature potentially important sequence patterns that appear in several established bio- and sensory-active peptides from independent sources, which suggests that our approach serves system-wide applicability. We generated a pattern peptide map and propose that in peptide glycation the herein identified molecular checkpoints can be used as indication of sequence reactivity.
Topics: Amino Acid Sequence; Gas Chromatography-Mass Spectrometry; Humans; Mass Spectrometry; Monosaccharides; Peptides
PubMed: 34168180
DOI: 10.1038/s41598-021-92413-7