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Biomacromolecules Apr 2023End-capped peptides modified with reactive functional groups on the N-terminus provide a route to prepare peptide-polymer conjugates for a broad range of applications....
End-capped peptides modified with reactive functional groups on the N-terminus provide a route to prepare peptide-polymer conjugates for a broad range of applications. Unfortunately, current chemical methods to construct modified peptides rely largely on solid-phase peptide synthesis (SPPS), which lacks green preparative characteristics and is costly, thus limiting its applicability to specialty applications such as regenerative medicine. This work evaluates N-terminally modified -acryloyl-glutamic acid diethyl ester, -acryloyl-leucine ethyl ester, and -acryloyl-alanine ethyl ester as grafters and papain as the protease for the direct addition of amino acid ethyl ester (AA-OEt) monomers via protease-catalyzed peptide synthesis (PCPS) and the corresponding formation of -acryloyl-functionalized oligopeptides in a one-pot aqueous reaction. It was hypothesized that by building -acryloyl grafters from AA-OEt monomers that are known to be good substrates for papain in PCPS, the corresponding grafters would yield high grafter conversions, high ratio of grafter-oligopeptide to free NH-oligopeptide, and high overall yield. However, this work demonstrates based on the grafter/monomers studied herein that the dominant factor in -acryloyl-AA-OEt grafter conversion is the co-monomer used in co-oligomerizations. Computational modeling using Rosetta qualitatively recapitulates the results and provides insight into the structural and energetic bases underlying substrate selectivity. The findings herein expand our knowledge of factors that determine the efficiency of preparing -acryloyl-terminated oligopeptides by PCPS that could provide practical routes to peptide macromers for conjugation to polymers and surfaces for a broad range of applications.
Topics: Amino Acids; Peptide Hydrolases; Papain; Peptides; Oligopeptides; Polymers; Catalysis; Esters
PubMed: 36996092
DOI: 10.1021/acs.biomac.3c00029 -
Neurogastroenterology and Motility Mar 2015Synthetic ghrelin agonists, predominantly small molecules, are being developed as prokinetic agents that may prove useful in the treatment of gastrointestinal motility... (Review)
Review
BACKGROUND
Synthetic ghrelin agonists, predominantly small molecules, are being developed as prokinetic agents that may prove useful in the treatment of gastrointestinal motility disorders. Relamorelin (RM-131) is a pentapeptide synthetic ghrelin analog that activates the growth hormone secretagogue (GHS)-1a (also called the ghrelin) receptor with approximately sixfold greater potency than natural ghrelin. The ability of relamorelin to stimulate growth hormone (GH) release is comparable to that of native ghrelin. Relamorelin has enhanced efficacy and plasma stability compared to native ghrelin.
PURPOSE
In this review, we discuss the pharmacokinetics, pharmacodynamics and potential indications for relamorelin. Relamorelin is administered subcutaneously, dosed daily or twice daily. Relamorelin is being studied for the treatment of patients with gastrointestinal motility disorders. Phase IIA pharmacodynamic studies have demonstrated acceleration of gastric emptying in patients with type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) and upper gastrointestinal symptoms. In a phase IIA study in patients with diabetic gastroparesis, relamorelin accelerated gastric emptying and significantly improved vomiting frequency compared to placebo and improved other symptoms of gastroparesis in a prespecified subgroup of patients with vomiting at baseline. In patients with chronic idiopathic constipation with defined transit profile at baseline, relamorelin relieved constipation and accelerated colonic transit compared to placebo. These characteristics suggest that this new ghrelin analog shows great promise to relieve patients with upper or lower gastrointestinal motility disorders.
Topics: Animals; Constipation; Gastrointestinal Diseases; Gastrointestinal Motility; Gastroparesis; Ghrelin; Humans; Oligopeptides; Treatment Outcome
PubMed: 25545036
DOI: 10.1111/nmo.12490 -
Cell Jan 2019Trypanosome parasites control their virulence and spread by using quorum sensing (QS) to generate transmissible "stumpy forms" in their host bloodstream. However, the QS...
Trypanosome parasites control their virulence and spread by using quorum sensing (QS) to generate transmissible "stumpy forms" in their host bloodstream. However, the QS signal "stumpy induction factor" (SIF) and its reception mechanism are unknown. Although trypanosomes lack G protein-coupled receptor signaling, we have identified a surface GPR89-family protein that regulates stumpy formation. TbGPR89 is expressed on bloodstream "slender form" trypanosomes, which receive the SIF signal, and when ectopically expressed, TbGPR89 drives stumpy formation in a SIF-pathway-dependent process. Structural modeling of TbGPR89 predicts unexpected similarity to oligopeptide transporters (POT), and when expressed in bacteria, TbGPR89 transports oligopeptides. Conversely, expression of an E. coli POT in trypanosomes drives parasite differentiation, and oligopeptides promote stumpy formation in vitro. Furthermore, the expression of secreted trypanosome oligopeptidases generates a paracrine signal that accelerates stumpy formation in vivo. Peptidase-generated oligopeptide QS signals being received through TbGPR89 provides a mechanism for both trypanosome SIF production and reception.
Topics: Cell Differentiation; Conserved Sequence; GTP-Binding Proteins; Membrane Transport Proteins; Oligopeptides; Phylogeny; Protozoan Proteins; Quorum Sensing; Signal Transduction; Trypanosoma; Trypanosoma brucei brucei; Trypanosomiasis, African; Virulence
PubMed: 30503212
DOI: 10.1016/j.cell.2018.10.041 -
Clinical Interventions in Aging 2009Degarelix is a gonadotropin-releasing hormone (GnRH) antagonist for the treatment of patients with prostate cancer in whom hormonal therapy is indicated. Two phase II... (Review)
Review
Degarelix is a gonadotropin-releasing hormone (GnRH) antagonist for the treatment of patients with prostate cancer in whom hormonal therapy is indicated. Two phase II trials and one phase III have been published as full papers in the literature. In the dose-finding phase II studies an initial dose of 240 mg degarelix sc followed by a monthly injection of 80 mg or 160 mg degarelix sc was sufficient to keep testosterone levels < or = 0.5 ng/ml. In a phase III trial it was demonstrated that degarelix was not inferior (in terms of testosterone suppression and prostate-specific antigen [PSA] decline) compared to standard hormonal therapy, ie, a GnRH agonist such as leuprolide. In fact, degarelix was associated with a faster testosterone suppression and PSA decline than leuprolide. Adverse events such as injection site reactions (40% vs <1%) and chills (4% vs 0%) were more commonly associated with degarelix. Also, degarelix is currently only available as one-month depot whereas in daily practice three-month depots (of GnRH agonists) are the preferred regimen. However, degarelix was recently approved by the US Food and Drug Administration for the treatment of advanced prostate cancer.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Middle Aged; Oligopeptides; Prostatic Neoplasms; Randomized Controlled Trials as Topic
PubMed: 19503784
DOI: 10.2147/cia.s3503 -
PloS One 2017'Superbug' bacteria producing NDM-1 enzyme causing wide public concern were first detected in a patient who visited India in 2008. It's an effective approach to...
'Superbug' bacteria producing NDM-1 enzyme causing wide public concern were first detected in a patient who visited India in 2008. It's an effective approach to combining β-lactam antibiotics with NDM-1 inhibitor for treating NDM-1 producing strain infection. In our research, we designed ten oligopeptides, tested IC50 values against NDM-1 enzyme, determined the MIC values of synergistic antibacterial effect and explored the binding model. We found that the oligopeptides 2 (Cys-Phe) and 5 (Cys-Asp) respectively presented IC50 values of 113 μM and 68 μM and also displayed favorable synergistic effects of the inhibitors in combination with ertapenem against genetic engineering-host E. coli BL21 (DE3)/pET30a-NDM-1 and a clinical isolate of P. aeruginosa with blaNDM-1. Flexible docking and partial charge study suggested the interaction between oligopeptide and NDM-1. Three types of action effects, hydrogen bond, electrostatic effect and π-π interaction, contributed to the inhibitory activities.
Topics: Anti-Bacterial Agents; Catalytic Domain; Drug Synergism; Enzyme Inhibitors; Ertapenem; Escherichia coli; Hydrogen Bonding; Ions; Molecular Docking Simulation; Molecular Structure; Oligopeptides; Protein Binding; Pseudomonas aeruginosa; Static Electricity; Water; Zinc; beta-Lactamases; beta-Lactams
PubMed: 28542279
DOI: 10.1371/journal.pone.0177293 -
BMC Biology Feb 2013Methanobactins (Mbns) are a family of copper-binding natural products involved in copper uptake by methanotrophic bacteria. The few Mbns that have been structurally...
BACKGROUND
Methanobactins (Mbns) are a family of copper-binding natural products involved in copper uptake by methanotrophic bacteria. The few Mbns that have been structurally characterized feature copper coordination by two nitrogen-containing heterocycles next to thioamide groups embedded in a peptidic backbone of varying composition. Mbns are proposed to derive from post-translational modification of ribosomally synthesized peptides, but only a few genes encoding potential precursor peptides have been identified. Moreover, the relevance of neighboring genes in these genomes has been unclear.
RESULTS
The potential for Mbn production in a wider range of bacterial species was assessed by mining microbial genomes. Operons encoding Mbn-like precursor peptides, MbnAs, were identified in 16 new species, including both methanotrophs and, surprisingly, non-methanotrophs. Along with MbnA, the core of the operon is formed by two putative biosynthetic genes denoted MbnB and MbnC. The species can be divided into five groups on the basis of their MbnA and MbnB sequences and their operon compositions. Additional biosynthetic proteins, including aminotransferases, sulfotransferases and flavin adenine dinucleotide (FAD)-dependent oxidoreductases were also identified in some families. Beyond biosynthetic machinery, a conserved set of transporters was identified, including MATE multidrug exporters and TonB-dependent transporters. Additional proteins of interest include a di-heme cytochrome c peroxidase and a partner protein, the roles of which remain a mystery.
CONCLUSIONS
This study indicates that Mbn-like compounds may be more widespread than previously thought, but are not present in all methanotrophs. This distribution of species suggests a broader role in metal homeostasis. These data provide a link between precursor peptide sequence and Mbn structure, facilitating predictions of new Mbn structures and supporting a post-translational modification biosynthetic pathway. In addition, testable models for Mbn transport and for methanotrophic copper regulation have emerged. Given the unusual modifications observed in Mbns characterized thus far, understanding the roles of the putative biosynthetic proteins is likely to reveal novel pathways and chemistry.
Topics: Amino Acid Sequence; Genome, Bacterial; Imidazoles; Molecular Sequence Data; Oligopeptides; Sequence Homology, Amino Acid
PubMed: 23442874
DOI: 10.1186/1741-7007-11-17 -
Physiological and transcriptome analysis of in response to X33 antimicrobial oligopeptide treatment.Frontiers in Cellular and Infection... 2023is an opportunistic pathogenic fungus, which frequently causes systemic or local fungal infections in . The evolution of its drug-resistant mutants necessitate an...
INTRODUCTION
is an opportunistic pathogenic fungus, which frequently causes systemic or local fungal infections in . The evolution of its drug-resistant mutants necessitate an urgent development of novel antimicrobial agents.
RESULTS
Here, we explored the antimicrobial activity and inhibitory mechanisms of X33 antimicrobial oligopeptide (X33 AMOP) against . The oxford cup test results showed that X33 AMOP had strong inhibitory activity against , and its MIC and MFC were 0.625 g/L and 2.5 g/L, respectively. Moreover, SEM and TEM showed that X33 AMOP disrupted the integrity of cell membrane. The AKP, ROS, HO and MDA contents increased, while the reducing sugar, soluble protein, and pyruvate contents decreased after the X33 AMOP treatment. This indicated that X33 AMOP could damage the mitochondrial integrity of the cells, thereby disrupting the energy metabolism by inducing oxidative stress in . Furthermore, transcriptome analysis showed that X33 AMOP treatment resulted in the differential expression of 1140 genes, among which 532 were up-regulated, and 608 were down-regulated. These DEGs were related to protein, nucleic acid, and carbohydrate metabolism, and their expression changes were consistent with the changes in physiological characteristics. Moreover, we found that X33 AMOP could effectively inhibit the virulence attributes of by reducing phospholipase activity and disrupting hypha formation.
DISCUSSION
These findings provide the first-ever detailed reference for the inhibitory mechanisms of X33 AMOP against and suggest that X33 AMOP is a potential drug candidate for treating infections.
Topics: Humans; Candida albicans; Hydrogen Peroxide; Antifungal Agents; Gene Expression Profiling; Anti-Infective Agents; Oligopeptides
PubMed: 36743308
DOI: 10.3389/fcimb.2023.1123393 -
Molecular Pharmaceutics Apr 2013The aim of this study was to determine the expression and function of proton-coupled oligopeptide transporters (POTs) in spleen and macrophages and their contribution to...
The aim of this study was to determine the expression and function of proton-coupled oligopeptide transporters (POTs) in spleen and macrophages and their contribution to innate immune response induced by bacterial peptidomimetics γ-iE-DAP and MDP. Quantitative real-time PCR (qRT-PCR) and Western blot results revealed the mRNA and protein expression of PepT2, PhT1, and PhT2, but not PepT1, in the spleen of mice and humans. In comparison to lymphocytes of the spleen, macrophages had higher transcript levels of PepT2 and PhT2. The cellular uptake of Ala-Lys-AMCA in mouse splenic macrophages was pH-dependent with maximum uptake at pH 6.0, and the kinetic parameters were K(m) = 75.5 ± 14.3 μM and V(max) = 25.4 ± 2.1 pmol/min per mg protein. The uptake of Ala-Lys-AMCA by mouse splenic macrophages was not inhibited by histidine but was significantly inhibited by glycyl-sarcosine (GlySar) and carnosine (P < 0.01), and by bacterial peptidomimetics γ-iE-DAP and MDP, ligands of nucleotide-binding oligomerization domain (NOD)-containing proteins. Carnosine and GlySar, but not histidine, attenuated the inflammatory response induced by γ-iE-DAP and MDP in mouse splenic macrophages. Functional expression of POTs was also demonstrated in THP-1 cells, and dipeptides reduced the immune response induced by γ-iE-DAP. In conclusion, our findings are novel by providing important information on the molecular and functional expression of POTs in the spleen. Moreover, it appears that the PepT2-mediated uptake of γ-iE-DAP and MDP in macrophages further contributes to the innate immune response.
Topics: Animals; Cell Line, Tumor; Dipeptides; Histidine; Humans; Hydrogen-Ion Concentration; Inflammation; Kinetics; Lymphocytes; Macrophages; Mice; Mice, Inbred ICR; Oligopeptides; Peptidomimetics; Rabbits; Real-Time Polymerase Chain Reaction; Species Specificity; Spleen; Symporters
PubMed: 23442152
DOI: 10.1021/mp300700p -
Scientific Reports Mar 2017Establishing cultures of human embryonic (ES) and induced pluripotent (iPS) stem cells in xeno-free conditions is essential for producing clinical-grade cells....
Establishing cultures of human embryonic (ES) and induced pluripotent (iPS) stem cells in xeno-free conditions is essential for producing clinical-grade cells. Development of cell culture biomaterials for human ES and iPS cells is critical for this purpose. We designed several structures of oligopeptide-grafted poly (vinyl alcohol-co-itaconic acid) hydrogels with optimal elasticity, and prepared them in formations of single chain, single chain with joint segment, dual chain with joint segment, and branched-type chain. Oligopeptide sequences were selected from integrin- and glycosaminoglycan-binding domains of the extracellular matrix. The hydrogels grafted with vitronectin-derived oligopeptides having a joint segment or a dual chain, which has a storage modulus of 25 kPa, supported the long-term culture of human ES and iPS cells for over 10 passages. The dual chain and/or joint segment with cell adhesion molecules on the hydrogels facilitated the proliferation and pluripotency of human ES and iPS cells.
Topics: Cell Differentiation; Cells, Cultured; Embryonic Stem Cells; Humans; Hydrogels; Oligopeptides; Pluripotent Stem Cells; Protein Binding; Protein Interaction Domains and Motifs
PubMed: 28332572
DOI: 10.1038/srep45146 -
Organogenesis Apr 2016WKYMVm hexapeptide has been identified as a strong FPR2 agonist through a library screening of synthetic peptides. The FPR2 has been reported to play a crucial role in...
WKYMVm hexapeptide has been identified as a strong FPR2 agonist through a library screening of synthetic peptides. The FPR2 has been reported to play a crucial role in inflammation and angiogenic responses via stimulation of chemotaxis, migration, cell proliferation, wound healing and vessel growth. Recently, the therapeutic effects of WKYMVm have been reported in various disease models. In cutaneous wound model in diabetic mice, WKYMVm facilitated wound healing processes by stimulating the formation of capillary and arteriole and re-epithelialization. In coronary artery stenosis model, WKYMVm coating on stent promoted re-endothelialization and lowered restenosis rate. In hindlimb ischemia mouse model, intramuscular injection of WKYMVm promoted homing of exogenously transplanted endothelial colony-forming cells and neovascularization, resulting in salvaging hindlimb. Furthermore, a single injection of WKYMVm encapsulated in poly (lactide-co-glycolide) microspheres was demonstrated to be as efficient as multiple injections of WKYMVm in restoring blood flow in hindlimb ischemia model. These observations may open up promising biomedical applications of WKYMVm for tissue repairs and regenerations.
Topics: Animals; Coronary Restenosis; Humans; Ischemia; Neovascularization, Physiologic; Oligopeptides; Skin; Stents; Wound Healing
PubMed: 27077939
DOI: 10.1080/15476278.2016.1172155