Intravascular delivery of an MK2 inhibitory peptide to prevent restenosis after angioplasty.

Peripheral artery disease is commonly treated with balloon angioplasty, a procedure involving minimally invasive, transluminal insertion of a catheter to the site of stenosis, where a balloon is inflated to open the blockage, restoring blood flow. However, peripheral angioplasty has a high rate of restenosis, limiting long-term patency. Therefore, angioplasty is sometimes paired with delivery of cytotoxic drugs like paclitaxel to reduce neointimal tissue formation. We pursue intravascular drug delivery strategies that target the underlying cause of restenosis - intimal hyperplasia resulting from stress-induced vascular smooth muscle cell switching from the healthy contractile into a pathological synthetic phenotype. We have established MAPKAP kinase 2 (MK2) as a driver of this phenotype switch and seek to establish convective and contact transfer (coated balloon) methods for MK2 inhibitory peptide delivery to sites of angioplasty. Using a flow loop bioreactor, we showed MK2 inhibition in ex vivo arteries suppresses smooth muscle cell phenotype switching while preserving vessel contractility. A rat carotid artery balloon injury model demonstrated inhibition of intimal hyperplasia following MK2i coated balloon treatment in vivo. These studies establish both convective and drug coated balloon strategies as promising approaches for intravascular delivery of MK2 inhibitory formulations to improve efficacy of balloon angioplasty.

Hypotensive effect of potent angiotensin-I-converting enzyme inhibitory peptides from corn gluten meal hydrolysate: Gastrointestinal digestion and transepithelial transportation modifications.

The study examined the antihypertensive effect of peptides derived from pepsin-hydrolyzed corn gluten meal, namely KQLLGY and PPYPW, and their in silico gastrointestinal tract digested fragments, KQL and PPY, respectively. KQLLGY and PPYPW showed higher angiotensin I-converting enzyme (ACE)-inhibitory activity and lower ACE inhibition constant (Ki) values when compared to KQL and PPY. Only KQL showed a mild antihypertensive effect in spontaneously hypertensive rats with -7.83 and - 5.71 mmHg systolic and diastolic blood pressure values, respectively, after 8 h oral administration. During passage through Caco-2 cells, KQL was further degraded to QL, which had reduced ACE inhibitory activity. In addition, molecular dynamics revealed that the QL-ACE complex was less stable compared to the KQL-ACE. This study reveals that structural transformation during peptide permeation plays a vital role in attenuating antihypertensive effect of the ACE inhibitor peptide.

Local and Systemic Peptide Therapies for Soft Tissue Regeneration: A Narrative Review.

Background: The musculoskeletal system, due to inherent structure and function, lends itself to contributing toward joint pain, whether from inflammatory disorders such as rheumatoid arthritis, degenerative diseases such as osteoarthritis, or trauma causing soft tissue injury. Administration of peptides for treatment of joint pain or inflammation is an emerging line of therapy that seeks to offer therapeutic benefits while remaining safe and relatively non-invasive. Purpose: The purpose of this study is to review the current literature on existing oral peptide agents, intra-articular peptide agents, and new developments in human trials to assess route of administration (RoA) for drug delivery in terms of soft tissue regeneration. Study Design: Narrative Review. Methods: A comprehensive literature search was conducted using the PubMed database. The search included medical subject headings (MeSH) terms related to peptide therapy, soft tissue regeneration, and RoA. Inclusion criteria comprised articles focusing on the mechanisms of action of peptides, clinical or biochemical outcomes, and review articles. Exclusion criteria included insufficient literature or studies not meeting the set evidence level. Conclusion: The review identified various peptides demonstrating efficacy in soft tissue repair. Oral and intra-articular peptides showed distinct advantages in soft tissue regeneration, with intra-articular routes providing localized effects and oral routes offering systemic benefits. However, both routes have limitations in bioavailability and absorption. Still in their infancy, further inquiries/research into the properties and efficacy of emerging peptides will be necessary before widespread use. As a viable alternative prior to surgical intervention, peptide treatments present as promising candidates for positive outcomes in soft tissue regeneration.

Phage libraries screening on P53: Yield improvement by zinc and a new parasites-integrating analysis.

P53 is a transcription factor that controls a variety of genes, primarily involved in cell cycle and other processes related to cell survival and death. We have isolated peptides targeting P53 (protein and domains) using the "phage display" technique. Interestingly, adding ZnCl2 at 5-10 mM in panning solutions helped to recover more plaque-forming units at least at round one of the screening. Subtractive docking analyses were designed by using a pool of common redundant peptides known as parasites. This rationale helped us differentiate between possibly specific and non-specific bindings. We found notable differences in docking characteristics between different sets of peptides either related to different targets or related to zinc-conditions. The set of zinc-related peptides shows advantageous docking profiles: sharper binding for some positions and distinct exclusive bound residues, including the relevant R248 and R273. Zinc would have modulating/helping role in the targeting of protein P53 by phage displayed peptides in addition to an enhancement action on bacterial infection.

Application of a modified multifunctional short peptide in the treatment of periodontitis.

Periodontitis is a chronic inflammatory disease involving plaque biofilm as a pathogenic factor. Potassium ion plays an important role in cellular homeostasis; a large outflow of potassium may lead to local inflammation progression. In this work, the multifunctional short peptide molecule BmKTX-33 was designed by modifying the BmKTX, a Kv1.3 potassium channel inhibitor. This was to explore its antibacterial properties, capability of maintaining cell ion homeostasis, and bone-forming capacity. The results showed that BmKTX-33 had inhibitory effects on S. gordonii, F. nucleatum, and P. gingivalis. Moreover, BmKTX-33 also inhibited excessive potassium outflow in inflammatory environments. Finally, BmKTX-33 promoted MC3T3-E1 early osteogenesis while suppressing the NLRP3 inflammasome's production. In conclusion, BmKTX-33 not only has antibacterial properties, but also can inhibit the expression of NLRP3 inflammasome and play an anti-inflammatory role.

Bioactive peptides from Tenebrio molitor: physicochemical and antioxidant properties and antimicrobial capacity.

Recent research has demonstrated the increasing interest in using insects for the extraction of bioactive compounds, particularly peptides. These compounds offer a spectrum of beneficial physiological effects. The aim of this study was to standardize a methodology for obtaining bioactive peptides from Tenebrio molitor and evaluate its physicochemical characterization, antioxidant, and antimicrobial potential. Six assays were carried out to hydrolyse larvae protein, with variations in Alcalase concentration (0.04 to 0.08%) and reaction time (3 to 8 h). The results indicated that the process applied to defatted mealworm flour was effective in reducing lipids by 82.5%. Consequently, it was an observed increase of 38.4% in protein content. Additionally, an increase in glycogen content was found in defatted mealworm flour (177 µmol glucose g-1 sample) and peptides (152.81 µmol glucose g-1 sample). The degree of hydrolysis was higher in assays with longer hydrolysis durations (8.14 - 8.38%). The antioxidant capacity was 12 to 14% lower in assays with an incubation time of 8h. In this sense, the methodology proposed in the present study proved to be efficient in obtaining bioactive peptides from T. molitor.

A Facile Method to Quantify Synthetic Peptide Concentrations on Biomaterials.

While it is well understood that peptides can greatly improve cell-material interactions, it is often challenging to determine the concentration of the peptide which decorates a material. Herein, we describe a straightforward method using readily, synthetically accessible Fmoc peptides and commercially available reagents to measure the concentration of peptides on nanoparticles, surfaces, and hydrogels. To achieve this, the Fmoc protecting group from immobilized peptides is removed under optimized basic conditions. The dibenzofulvene released can be quantified by HPLC or UV-vis spectroscopy, enabling a direct experimental measurement of the concentration of the peptide. We show that we can measure the concentration of a BMP-2 peptide mimic on a hydrogel to determine the concentration required to stimulate osteogenesis of human mesenchymal stem cells. We envision that this methodology will enable a more thorough understanding of the concentration of synthetic peptides decorated on many biomaterials (e.g., nanoparticles, surfaces, hydrogels) to improve deconvolution of the interactions at the cell-material interface.

Synthesis, Anti-TMV Activities, and Action Mechanisms of a Novel Cytidine Peptide Compound.

Cytidine has a broad range of applications in the pharmaceutical field as an intermediate of antitumor or antiviral agent. Here, a series of new cytidine peptide compounds were synthesized using cytidine and Boc group-protected amino acids and analyzed for their antiviral activities against tobacco mosaic virus (TMV). Among these compounds, the structure of an effective antiviral cytidine peptide SN11 was characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometer. The compound SN11 has a molecular formula of C15H22N6O8 and is named 2-amino-N-(2- ((1- (3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl) -2-oxo-1,2-dihydropyrimidin-4-yl) amino) -2-oxyethyl) amino). The protection, inactivation, and curation activities of SN11 at a concentration of 500 µg/mL against TMV in Nicotiana glutinosa were 82.6%, 84.2%, and 72.8%, respectively. SN11 also effectively suppressed the systemic transportation of a recombinant TMV carrying GFP reporter gene (p35S-30B:GFP) in Nicotiana benthamiana by reducing viral accumulation to 71.3% in the upper uninoculated leaves and inhibited the systemic infection of TMV in Nicotiana tabacum plants. Furthermore, the results of RNA-seq showed that compound SN11 induced differential expression of genes involved in the biogenesis and function of ribosome, plant hormone signal transduction, plant pathogen interaction, and chromatin. These results validate the antiviral mechanisms of the cytidine peptide compound and provide a theoretical basis for their potential application in the management of plant virus diseases.

Peptide-Based Strategies: Combating Alzheimer's Amyloid ß Aggregation through Ergonomic Design and Fibril Disruption.

Amyloidosis of amyloid-ß (Aß) triggers a cascade of events, leading to oxidative damage and neuronal death. Therefore, inhibiting Aß amyloidosis or disrupting the matured fibrils is the primary target to combat progressive Alzheimer's disease (AD) pathogenesis. Here, we undertake optimization strategies to improve the antiamyloid efficiency of our previously reported NF11 (NAVRWSLMRPF) peptide. Among the series of peptides tested, nontoxic and serum-stable peptide 1 or P1 containing an anthranilic acid residue shows immense potential in not only inhibiting the Aß42 amyloid formation but also disrupting the mature Aß42 fibrils into nontoxic small molecular weight soluble species. Our studies provide high-resolution characterization of the peptide's mechanism of action. With a binding affinity within the micromolar range for both the monomer and aggregated Aß42, this α/ß hybrid peptide can efficiently modulate Aß amyloidosis while facilitating the clearance of toxic aggregates and enforcing protection from apoptosis. Thus, our studies highlight that incorporating a ß-amino acid not only imparts protection from proteolytic degradation and improved stability but also functions effectively as a ß breaker, redirecting the aggregation kinetics toward off-pathway fibrillation.

Zein and gum arabic nanoparticles: potential enhancers of immunomodulatory functional activity of selenium-containing peptides.

Food-derived nanomaterials optimizing bioactive peptides is an emerging route in the functional food field. Zein and gum arabic (GA) possess favorable encapsulation properties for controlled release, targeted delivery and stabilization of food bioactive ingredients, and thus are considered as promising carriers for delivery systems. In order to improve the bioavailability of rice selenium-containing peptide TSeMMM (T), the nanoparticles (ZTGNs) containing peptide T, zein and GA have been previously prepared. This study focused on evaluating the immunomodulatory capacity of ZTGNs. The results showed that ZTGNs significantly alleviated cyclophosphamide-induced reduction in immune organ indices and liver glutathione content of mice. There was a significant upregulation observed in the levels of immune-related cytokines IL-6, TNF-α, and IFN-γ as well as their mRNA expression. Moreover, ZTGNs enriched the diversity of the intestinal flora and promoted the proportion of beneficial bacteria. In conclusion, ZTGNs have potential as immunomodulatory enhancers for food bioactive ingredients, providing prospects for further optimization of dietary supplements.