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Journal of Controlled Release :... Aug 2023To reduce the mortality of myocardial infarction (MI), accurate detection of the infarct and appropriate prevention against ischemia/reperfusion (I/R) induced cardiac...
To reduce the mortality of myocardial infarction (MI), accurate detection of the infarct and appropriate prevention against ischemia/reperfusion (I/R) induced cardiac dysfunction are highly desired. Considering that vascular endothelial growth factor (VEGF) receptors are overexpressed in the infarcted heart and VEGF mimetic peptide QK binds specifically to VEGF receptors and activates vascularization, the PEG-QK-modified, gadolinium-doped carbon dots (GCD-PEG-QK) were formulated. This research aims to investigate the magnetic resonance imaging (MRI) capability of GCD-PEG-QK on myocardial infarct and their therapeutic effect on I/R-induced myocardial injury. These multifunctional nanoparticles exhibited good colloidal stability, excellent fluorescent and magnetic property, and satisfactory biocompatibility. Intravenous injection of GCD-PEG-QK nanoparticles post myocardial I/R displayed accurate MRI of the infarct, enhanced efficacy of QK peptide on pro-angiogenesis, and amelioration of cardiac fibrosis, remodeling and dysfunction, probably via the improvement on QK's in vivo stability and MI-targeting. Collectively, the data suggested that this theranostic nanomedicine can realize precise MRI and effective therapy for acute MI in a non-invasive manner.
Topics: Humans; Vascular Endothelial Growth Factor A; Peptides; Myocardial Infarction; Magnetic Resonance Imaging; Nanoparticles
PubMed: 37330014
DOI: 10.1016/j.jconrel.2023.06.017 -
Trends in Plant Science Aug 2023Diverse plant small peptides are perceived by their corresponding receptors to mediate local or long-distance intercellular communications in various developmental and...
Diverse plant small peptides are perceived by their corresponding receptors to mediate local or long-distance intercellular communications in various developmental and adaptive programs; notably, the mechanisms of peptide-receptor perception remain largely unrevealed. Two reports (Liu et al.; Diaz-Ardila et al.) shed light on how pH regulates peptide-receptor perception.
Topics: Peptides; Plants; Perception; Hydrogen-Ion Concentration
PubMed: 37150623
DOI: 10.1016/j.tplants.2023.04.015 -
Frontiers in Immunology 2023Our previous research has found that degradation of palmitoyltransferase in tumor cells using a linear peptide PROTAC leads to a significant decrease in PD-L1 expression...
INTRODUCTION
Our previous research has found that degradation of palmitoyltransferase in tumor cells using a linear peptide PROTAC leads to a significant decrease in PD-L1 expression in tumors. However, this degradation is not a sustained and efficient process. Therefore, we designed a cyclic peptide PROTAC to achieve this efficient anti-PD-L1 effect.
METHODS
We designed and synthesized an improvement in linear peptide PROTAC targeting palmitoyltransferase DHHC3, and used disulfide bonds to stabilize the continuous N- and C-termini of the peptides to maintain their structure. Cellular and molecular biology techniques were used to test the effect of this cyclic peptide on PD-L1.
RESULTS
In human cervical cancer cells, our cyclic peptide PROTAC can significantly downregulate palmitoyl transferase DHHC3 and PD-L1 expressions. This targeted degradation effect is enhanced with increasing doses and treatment duration, with a DC50 value much lower than that of linear peptides. Additionally, flow cytometry analysis of fluorescence intensity shows an increase in the amount of cyclic peptide entering the cell membrane with prolonged treatment time and higher concentrations. The Cellular Thermal Shift Assay (CETSA) method used in this study indicates effective binding between our novel cyclic peptide and DHHC3 protein, leading to a change in the thermal stability of the latter. The degradation of PD-L1 can be effectively blocked by the proteasome inhibitor MG132. Results from clone formation experiments illustrate that our cyclic peptide can enhance the proliferative inhibition effect of cisplatin on the C33A cell line. Furthermore, in the T cell-C33A co-culture system, cyclic peptides target the degradation of PD-L1, thereby blocking the interaction between PD-L1 and PD-1, and promoting the secretion of IFN-γ and TNF-α in the co-culture system supernatant.
CONCLUSION
Our results demonstrate that a disulfide-bridged cyclic peptide PROTAC targeting palmitoyltransferase can provide a stable and improved anti-PD-L1 activity in human tumor cells.
Topics: Female; Humans; Peptides, Cyclic; Uterine Cervical Neoplasms; B7-H1 Antigen; Cell Line, Tumor; Peptides; Transferases; Disulfides
PubMed: 37849747
DOI: 10.3389/fimmu.2023.1237964 -
Langmuir : the ACS Journal of Surfaces... Aug 2023Lipid bilayer membranes are often represented as a continuous nonpolar slab with a certain thickness bounded by two more polar interfaces. Phenomena such as peptide... (Review)
Review
Lipid bilayer membranes are often represented as a continuous nonpolar slab with a certain thickness bounded by two more polar interfaces. Phenomena such as peptide binding to the membrane surface, folding, insertion, translocation, and diffusion are typically interpreted on the basis of this view. In this Perspective, I argue that this membrane representation as a hydrophobic continuum solvent is not adequate to understand peptide-lipid interactions. Lipids are not small compared to membrane-active peptides: their sizes are similar. Therefore, peptide diffusion needs to be understood in terms of free volume, not classical continuum mechanics; peptide solubility or partitioning in membranes cannot be interpreted in terms of hydrophobic mismatch between membrane thickness and peptide length; peptide folding and translocation, often involving cationic peptides, can only be understood if realizing that lipids adapt to the presence of peptides and the membrane may undergo considerable lipid redistribution in the process. In all of those instances, the detailed molecular interactions between the peptide residues and the lipid components are essential to understand the mechanisms involved.
Topics: Peptides; Lipid Bilayers; Biophysical Phenomena
PubMed: 37478368
DOI: 10.1021/acs.langmuir.3c00538 -
Viruses Apr 2024Phage display is a versatile method often used in the discovery of peptides that targets disease-related biomarkers. A major advantage of this technology is the ease and... (Review)
Review
Phage display is a versatile method often used in the discovery of peptides that targets disease-related biomarkers. A major advantage of this technology is the ease and cost efficiency of affinity selection, also known as biopanning, to identify novel peptides. While it is relatively straightforward to identify peptides with optimal binding affinity, the pharmacokinetics of the selected peptides often prove to be suboptimal. Therefore, careful consideration of the experimental conditions, including the choice of using in vitro, in situ, or in vivo affinity selections, is essential in generating peptides with high affinity and specificity that also demonstrate desirable pharmacokinetics. Specifically, in vivo biopanning, or the combination of in vitro, in situ, and in vivo affinity selections, has been proven to influence the biodistribution and clearance of peptides and peptide-conjugated nanoparticles. Additionally, the marked difference in properties between peptides and nanoparticles must be considered. While peptide biodistribution depends primarily on physiochemical properties and can be modified by amino acid modifications, the size and shape of nanoparticles also affect both absorption and distribution. Thus, optimization of the desired pharmacokinetic properties should be an important consideration in biopanning strategies to enable the selection of peptides and peptide-conjugated nanoparticles that effectively target biomarkers in vivo.
Topics: Peptides; Animals; Cell Surface Display Techniques; Humans; Tissue Distribution; Nanoparticles; Peptide Library
PubMed: 38675913
DOI: 10.3390/v16040570 -
Journal of Medicinal Chemistry Feb 2024Building on recent advances in peptide science, medicinal chemists have developed a hybrid class of bioconjugates, called peptide-drug conjugates, that demonstrate... (Review)
Review
Building on recent advances in peptide science, medicinal chemists have developed a hybrid class of bioconjugates, called peptide-drug conjugates, that demonstrate improved efficacy compared to peptides and small molecules independently. In this Perspective, we discuss how the conjugation of synergistic peptides and small molecules can be used to overcome complex disease states and resistance mechanisms that have eluded contemporary therapies because of their multi-component activity. We highlight how peptide-drug conjugates display a multi-factor therapeutic mechanism similar to that of antibody-drug conjugates but also demonstrate improved therapeutic properties such as less-severe off-target effects and conjugation strategies with greater site-specificity. The many considerations that go into peptide-drug conjugate design and optimization, such as peptide/small-molecule pairing and chemo-selective chemistries, are discussed. We also examine several peptide-drug conjugate series that demonstrate notable activity toward complex disease states such as neurodegenerative disorders and inflammation, as well as viral and bacterial targets with established resistance mechanisms.
Topics: Immunoconjugates; Antigens; Peptides; Drug Design
PubMed: 38277480
DOI: 10.1021/acs.jmedchem.3c01835 -
Angewandte Chemie (International Ed. in... Aug 2023Herein, we report a novel strategy for the modification of peptides based on the introduction of highly reactive hypervalent iodine reagents-ethynylbenziodoxolones...
Herein, we report a novel strategy for the modification of peptides based on the introduction of highly reactive hypervalent iodine reagents-ethynylbenziodoxolones (EBXs)-onto peptides. These peptide-EBXs can be readily accessed, by both solution- and solid-phase peptide synthesis (SPPS). They can be used to couple the peptide to other peptides or a protein through reaction with Cys, leading to thioalkynes in organic solvents and hypervalent iodine adducts in water buffer. Furthermore, a photocatalytic decarboxylative coupling to the C-terminus of peptides was developed using an organic dye and was also successful in an intramolecular fashion, leading to macrocyclic peptides with unprecedented crosslinking. A rigid linear aryl alkyne linker was essential to achieve high affinity for Keap1 at the Nrf2 binding site with potential protein-protein interaction inhibition.
Topics: Indicators and Reagents; Kelch-Like ECH-Associated Protein 1; Iodine; NF-E2-Related Factor 2; Peptides
PubMed: 37311172
DOI: 10.1002/anie.202306036 -
Cell Chemical Biology Jul 2023Inhibition of protein-protein interactions (PPIs) via designed peptides is an effective strategy to perturb their biological functions. The Elongin BC heterodimer...
Inhibition of protein-protein interactions (PPIs) via designed peptides is an effective strategy to perturb their biological functions. The Elongin BC heterodimer (ELOB/C) binds to a BC-box motif and is essential for cancer cell growth. Here, we report a peptide that mimics the high-affinity BC-box of the PRC2-associated protein EPOP. This peptide tightly binds to the ELOB/C dimer (k = 0.46 ± 0.02 nM) and blocks the association of ELOB/C with its interaction partners, both in vitro and in the cellular environment. Cancer cells treated with our peptide inhibitor showed decreased cell viability, increased apoptosis, and perturbed gene expression. Therefore, our work proposes that blocking the BC-box-binding pocket of ELOB/C is a feasible strategy to impair its function and inhibit cancer cell growth. Our peptide inhibitor promises novel mechanistic insights into the biological function of the ELOB/C dimer and offers a starting point for therapeutics linked to ELOB/C dysfunction.
Topics: Elongin; Transcription Factors; Protein Binding; Peptides; Apoptosis; Ubiquitin-Protein Ligases; Neoplasms
PubMed: 37354906
DOI: 10.1016/j.chembiol.2023.05.012 -
Biochemical Pharmacology Nov 2023GPR81, initially discovered in adipocytes, has been found to suppress lipolysis when activated. However, the current small molecules that target GPR81 carry the risk of...
GPR81, initially discovered in adipocytes, has been found to suppress lipolysis when activated. However, the current small molecules that target GPR81 carry the risk of off-target effects, and their impact on tumor progression remains uncertain. Here, we utilized phage display technology to screen a GPR81-targeting peptide named 7w-2 and proceeded to demonstrate its bioactivity. Although 7w-2 did not affect the proliferation of tumor cells, it effectively reduced adipocyte catabolism in vitro, consequently restraining the proliferation of co-cultured tumor cells. Furthermore, our findings revealed that 7w-2 could inhibit lipolysis in vivo, leading to a significant impediment in tumor growth and metastasis in the 4T1 murine tumor model. Additionally, 7w-2 exhibited the ability to significantly elevate the proportion and functionality of CD8 T cells. Our study introduces 7w-2 as the first peptide targeting GPR81, shedding light on its potential role in adipocytes in suppressing tumor progression.
Topics: Mice; Animals; Receptors, G-Protein-Coupled; CD8-Positive T-Lymphocytes; Adipocytes; Lipolysis; Peptides
PubMed: 37696459
DOI: 10.1016/j.bcp.2023.115800 -
Biomolecules Jul 2023Myofibroblasts are the principal effector cells driving fibrosis, and their accumulation in tissues is a fundamental feature of fibrosis. Essential pathways have been... (Review)
Review
Myofibroblasts are the principal effector cells driving fibrosis, and their accumulation in tissues is a fundamental feature of fibrosis. Essential pathways have been identified as being central to promoting myofibroblast differentiation, revealing multiple targets for intervention. Compared with large proteins and antibodies, peptide-based therapies have transpired to serve as biocompatible and cost-effective solutions to exert biomimicry, agonistic, and antagonistic activities with a high degree of targeting specificity and selectivity. In this review, we summarize emergent antifibrotic peptides and their utilization for the targeted prevention of myofibroblasts. We then highlight recent studies on peptide inhibitors of upstream pathogenic processes that drive the formation of profibrotic cell phenotypes. We also briefly discuss peptides from non-mammalian origins that show promise as antifibrotic therapeutics. Finally, we discuss the future perspectives of peptide design and development in targeting myofibroblasts to mitigate fibrosis.
Topics: Myofibroblasts; Peptides; Antibodies; Cell Differentiation
PubMed: 37627244
DOI: 10.3390/biom13081179