Peptide Compounds Research Articles

Candida albicans cell wall as a target of action for the protein\u2013carbohydrate fraction from coelomic fluid of Dendrobaena veneta

The protein–polysaccharide fraction (AAF) isolated from the coelomic fluid of the earthworm Dendrobaena veneta destroys C. albicans cells by changing their morphology, disrupting cell division, and leading to cell death. Morphological changes in C. albicans cells induced by treatment with AAF were documented using DIC, SEM, and AFM. Congo Red staining showed that the fungal wall structure was changed after incubation with AAF. The effect on C. albicans cell walls was shown by AFM analysis of the surface roughness of fungal cell walls and changes in the wall thickness were visualized using Cryo-SEM. The FTIR analysis of C. albicans cells incubated with AAF indicated attachment of protein or peptide compounds to the fungal walls. The intact LC–ESI–MS analysis allowed accurate determination of the masses of molecules present in AAF. As shown by the chromatographic study, the fraction does not cross biological membranes. The Cryo-TEM analysis of AAF demonstrated the ability of smaller subunits to combine into larger agglomerates. AAF is thermally stable, which was confirmed by Raman spectroscopy. AAF can be considered as a potential antifungal antibiotic with activity against clinical C. albicans strains.

The protective effects of C16 peptide and angiopoietin-1 compound in lipopolysaccharide-induced acute respiratory distress syndrome.

C16 peptide and angiopoietin-1 (Ang-1) have been found to have anti-inflammatory activity in various inflammation-related diseases. However, their combined role in acute respiratory distress syndrome (ARDS) has not been investigated yet. The objective of this study was to investigate the effects of C16 peptide and Ang-1 in combination with lipopolysaccharide (LPS)-induced inflammatory insult in vitro and in vivo. Human pulmonary microvascular endothelial cells and human pulmonary alveolar epithelial cells were used as cell culture systems, and an ARDS rodent model was used for in vivo studies. Our results demonstrated that C16 and Ang-1 in combination significantly suppressed inflammatory cell transmigration by 33% in comparison with the vehicle alone, and decreased the lung tissue wet-to-dry lung weight ratio to a maximum of 1.53, compared to 3.55 in the vehicle group in ARDS rats. Moreover, C + A treatment reduced the histology injury score to 60% of the vehicle control, enhanced arterial oxygen saturation (SO2), decreased arterial carbon dioxide partial pressure (PCO2), and increased oxygen partial pressure (PO2) in ARDS rats, while also improving the survival rate from 47% (7/15) to 80% (12/15) and diminishing fibrosis, necrosis, and apoptosis in lung tissue. Furthermore, when C + A therapy was administered 4 h following LPS injection, the treatment showed significant alleviating effects on pulmonary inflammatory cell infiltration 24 h postinsult. In conclusion, our in vitro and in vivo studies show that C16 and Ang-1 exert protective effects against LPS-induced inflammatory insult. C16 and Ang-1 hold promise as a novel agent against LPS-induced ARDS. Further studies are needed to determine the potential for C16 and Ang-1 in combination in treating inflammatory lung diseases.

Identification of Novel Peptides Targeting DNA Methyltransferase 1 (DNMT-1) for Breast Cancer Treatment

Epigenetic alteration shows an essential role in the process of breast cancer cell proliferation and propagation. DNA methyltransferase (DNMT) is responsible for DNA methylation, resulted in the epigenetic silencing of multiple genes. Hence, inhibiting DNMT-1 is a promising way to block uncontrolled DNA methylation. This study aimed to retrieve a potential peptide compound as DNMT-1 inhibitor due to its desirable properties as drug candidate through virtual screening and molecular docking simulation. A total of 51,957 peptide ligands from PubChem database underwent computational pharmacological screening to eliminate compounds with undesired characteristics. Molecular docking simulation was done with generated pharmacophore features, and the potential ligands with good ΔG binding, RMSD value, and molecular interaction were cyclized to increase the bioavailability of the peptides. Cyclic peptide ligands were tested for its interaction with DNMT-1 protein and ADME-Tox properties. From these steps, three cyclic peptide ligands showed desirable characteristics as a new drug candidate for the DNMT1 inhibitor.

Advances of CCR5 antagonists: From small molecules to macromolecules.

C-C chemokine receptor 5(CCR5) is a cell membrane protein from G protein-coupled receptors (GPCR) family, which is an important modulator for leukocyte activation and mobilization. In the 1980s, several reports suggest that lack of the HIV-1 co-receptor, the chemokine receptor CCR5, offers protection against HIV infection. Later, it was shown that CCR5 was confirmed to be the most common co-receptor for the HIV-1 virus R5 strain. In recent years, many studies have shown that CCR5 is closely related to the development of various cancers and inflammations to facilitate the discovery of CCR5 antagonists. There are many types of CCR5 antagonists, mainly including chemokine derivatives, non-peptide small molecule compounds, monoclonal antibodies, and peptide compounds. This review focus on the recent research processes and pharmacological effects of CCR5 antagonists such as Maraviroc, TAK-779 and PRO 140. After focusing on the therapeutic effect of CCR5 antagonists on AIDS, it also discusses the therapeutic prospect of CCR5 in other diseases such as inflammation and tumor.

Abstract 2984: Developing a new combinational therapy to combat temozolomide resistance in glioblastoma multiforme

Abstract Background: Glioblastoma multiforme (GBM) is the most lethal central nervous system malignancy, and recurrence is seen in nearly all cases. Temozolomide (TMZ), a DNA alkylating agent, shows initial promise in eradicating primary GBM, but has little effect on recurrent GBM. Our previous work identified the Phosphatidylinositol 3-kinase Catalytic Subunit Beta (PIK3CB) of the PI3K pathway to be selectively important for the survival and progression of GBM (1). Other previous research also shows that a gap-junction protein, Connexin 43 (Cx43), promotes TMZ resistance in GBM by activating PI3K signaling and that this resistance can be reversed by treatment with a peptide compound named αCT1 (2). More recently, it was discovered that G-protein coupled receptors (GPCRs), specifically the Gβγ subunit, are upstream activators of Cx43/PI3K/AKT signaling in TMZ-resistant GBM cells. We believe that selectively targeting and blocking the activators of these signaling pathways will help to restore and enhance sensitivity to TMZ, yielding successful eradication of GBM cells. We therefore propose to test the effect of a quadruple combination of TMZ, αCT1, TGX-221, and gallein, a selective inhibitor of the Gβγ subunit of GPCRs, on GBM tumor growth. Hypothesis: Gβγ subunit inhibition will substantially increase GBM cytotoxicity in combination with αCT1, TGX-221 (a PIK3CB inhibitor), and TMZ. Methods: MTS cell viability assay was used to determine optimum gallein dosage both alone and in combinational therapies in experimental cell lines with variable Cx43 expression rates and TMZ sensitivities. This assay was also used to determine cell viability after treatment with an optimized quadruple combination therapy in these same lines. Current work is focused on quantifying Cx43/PIK3CB/AKT signaling inhibition via Western blot, as well as applying the optimized quadruple combination treatment in GBM stem cells, three-dimensional GBM tumor models, primary GBM patient samples, and healthy astrocytes. Results: Significant inhibitory effects have been shown with an optimized quadruple combination therapy compared to TMZ alone in TMZ-resistant experimental cell lines. Conclusions: While results in experimental lines have been favorable, additional work is still needed to elucidate the efficacy of the optimized quadruple combination therapy, which will include testing primary GBM patient samples, GBM stem cells, healthy astrocytes and three-dimensional tumor models.

Abstract 3006: Anticancer and multidrug resistance-reversing activities of novel antimicrobial peptides

Abstract Cancer is a growing concern in public health problems worldwide. Although the development of advanced chemotherapies has already partly reduced the cancer death rate and improved patients' prognosis, the phenomenon of multidrug resistance (MDR), which impairs the efficacy of a serial structure-unrelated anticancer agent, casts a large shadow over the bright future of chemotherapies. MDR has various mechanisms to induce acquired drug resistance of cancer cells after a relatively long period of chemotherapy. One of the most common causes of MDR is the expression of ATP-binding cassette (ABC) transporters, which act as efflux pumps on cancer cell membranes and transport anticancer drugs out of cancer cells thereby reducing the intracellular drug concentration. The growing resistance of cancer cells to current anticancer drugs leads to the urgent need to develop anticancer drugs with a new mechanism of action. Over the past decade, antimicrobial peptides have entered the view of scientists as a new generation of anticancer drugs. In this study, the anticancer effects and the reversal activities against ABC transporter mediated MDR of four novel antimicrobial peptides were investigated. The results showed that, at non-toxic concentrations in vitro, peptides #7, #14, #22, and #24 significantly sensitized ABCB1- and ABCC1-overexpressing cell lines, including both drug-selected MDR cancer cell lines and ABCB1 or ABCC1 gene transfected HEK293 cell lines, to the substrate anticancer drugs paclitaxel and vincristine. Among the antimicrobial peptide compounds, #14 and #24 with the most potent reversal ability were selected for further investigation. These peptides increased the intracellular accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells and that of [3H]-vincristine in ABCC1 overexpressing cells by suppressing the efflux function of ABCB1 and ABCC1 transporters, without causing alteration in the expression levels and localization patterns of ABCB1 and ABCC1 in overexpressing cells. Furthermore, the results of the ATPase assay showed that both two peptides stimulated ABCB1 ATPase activity. Taken together, these results demonstrated that peptide #14 and #24 reverse ABCB1- and ABCC1-mediated MDR through blocking the function of ABCB1 and ABCC1 without affecting the transporters' expression and cellular localization, which suggests that antimicrobial peptides may be used as a novel prospective cancer therapeutic strategy in the combination with traditional anticancer agents. Citation Format: Qiu-Xu Teng, Zi-Ning Lei, Xiaofang Luo, Jing-Quan Wang, Zuodong Qin, John N. Wurpel, Zhe-Sheng Chen. Anticancer and multidrug resistance-reversing activities of novel antimicrobial peptides [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3006.

Research progress on small peptides in Chinese Baijiu

Abstract Chinese Baijiu is a distilled spirit with >100 health promoting compounds produced by diverse microorganisms through the fermentation process. Compared with other distilled spirits in the world, various small peptide compounds in Chinese Baijiu endow it with unparalleled health benefits. In this review, we summarize the small peptides that have been found in Chinese Baijiu, and we provide the unique physiological and pharmacological activity of these small peptides by reviewing recent research papers. Existing problems in current research on small peptides in Chinese Baijiu, and the direction and significance of future research are also discussed.

IDENTIFIKASI BIOKIMIA DAN AKTIVITAS ANTIBAKTERI ISOLAT BAKTERI ASAM LAKTAT DARI LIMBAH SAYUR SAWI (Brassica juncea L.)

Lactic Acid Bacteria (LAB) is a group of bacteria that produce lactic acid as the main product in carbohydrate fermentation. LAB has a major role to fight against pathogenic bacteria through peptide compounds. LAB can be found in vegetables that contain carbohydrates. The research objective was to determine biochemically and determine the antibacterial activity of LAB isolates from Brassica juncea L vegetable waste. Biochemical testing methods include TSIA, Indol, MR_VP, motility, temperature resistance and salt resistance tests. While testing the activity using the disc diffution method is used by the media Mueller Hinton Agar against Basillus subtilis , Escherichia coli , Staphylococcus aureus , Staphylococcus epidermidis , Streptococcus mutans , Salmonella thypimurium , and Propionibacterium acnes . Preparation of the test sample was carried out by inoculating LAB isolate stock for 1x24 hours at 37 ° C. Biochemical identification results showed that LAB isolates were able to ferment glucose, negative in indole and VP testing, positive in MR testing was characterized by obtaining acidic pH, non-motile nature, living at 37 ° C, and resistant to several salt concentrations (5-10%). The results of testing antibacterial activity based on univariate analysis showed differences in the activity of each of the test bacteria obtained p = 0,730 (p>0,05). LSD analysis showed no significant differences between all isolates. Conclusion: isolates obtained included LAB group from the family Lactobacillaceae, genus Lactobacillus sp and the antibacterial activity was broad spectrum

Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules

Hypertension is a diverse illness interlinked with cerebral, cardiovascular (CVS) and renal abnormalities. Presently, the malady is being treated by focusing on Renin- angiotensin system (RAS), voltage-gated calcium channels, peripheral vasodilators, renal and sympathetic nervous systems. Cardiovascular and renal abnormalities are associated with the overactivation of RAS, which can be constrained by angiotensin- converting enzyme inhibitors (ACEIs), angiotensin II (Ang-II) -AT1 receptor blockers (ARBs) and renin inhibitors. The latter is a new player in the old system. The renin catalyzes the conversion of angiotensinogen to Angiotensin I (Ang-I). This can be overcome by inhibiting renin, a preliminary step, eventually hinders the occurrence of the cascade of events in the RAS. Various peptidomimetics, the first-generation renin inhibitors developed six decades ago have limited drug-like properties as they suffered from poor intestinal absorption, high liver first-pass metabolism and low oral bioavailability. The development of chemically diverse molecules from peptides to nonpeptides expanded the horizon to achieving direct renin inhibition. Aliskiren, a blockbuster drug that emerged as a clinical candidate and got approved by the US FDA in 2007 was developed by molecular modeling studies. Aliskiren indicated superior to average efficacy and with minor adverse effects relative to other RAS inhibitors. However, its therapeutic use is limited by poor oral bioavailability of less than 2% that is similar to first-generation peptidic compounds. In this review, we present the development of direct renin inhibitors (DRIs) from peptidic to nonpeptidics that lead to the birth of aliskiren, its place in the treatment of cardiovascular diseases and its limitations.

The Neurokinins: Peptidomimetic Ligand Design and Therapeutic Applications.

The neurokinins are indisputably essential neurotransmitters in numerous pathoand physiological events. Being widely distributed in the Central Nervous System (CNS) and peripheral tissues, their discovery rapidly promoted them to drugs targets. As a necessity for molecular tools to understand the biological role of this class, endogenous peptides and their receptors prompted the scientific community to design ligands displaying either agonist and antagonist activity at the three main neurokinin receptors, called NK1, NK2 and NK3. Several strategies were implemented for this purpose. With a preference to small non-peptidic ligands, many research groups invested efforts in synthesizing and evaluating a wide range of scaffolds, but only the NK1 antagonist Aprepitant (EMENDT) and its prodrug Fosaprepitant (IVEMENDT) have been approved by the Food Drug Administration (FDA) for the treatment of Chemotherapy-Induced and Post-Operative Nausea and Vomiting (CINV and PONV, respectively). While non-peptidic drugs showed limitations, especially in side effect control, peptidic and pseudopeptidic compounds progressively regained attention. Various strategies were implemented to modulate affinity, selectivity and activity of the newly designed ligands. Replacement of canonical amino acids, incorporation of conformational constraints, and fusion with non-peptidic moieties gave rise to families of ligands displaying individual or dual NK1, NK2 and NK3 antagonism, that ultimately were combined with non-neurokinin ligands (such as opioids) to target enhanced biological impact.

In silico Identification of Peptide as Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Cancer Treatment.

Epidermal growth factor receptor (EGFR) is the biomarker for lung cancer in which the protein has the most active mutated genes in lung cancer patients. Peptides have pharmacological potential as drugs because of their bioactivity and accessibility. The research objective was to obtain peptide compounds drug candidates with good interaction and pharmacological properties that can act as an inhibitor for EGFR for lung cancer treatment by using in silico method. EGFR protein structure was obtained from Protein Data Bank and the peptide compounds were retrieved from PubChem. Optimization and energy minimization process were done to prepare the peptides for the simulation. Protein-Ligand Interaction Fingerprint (PLIF) was used to determine the pharmacophore features in the EGFR binding site. Both proteins and ligands underwent a virtual screening through rigid and flexible molecular docking simulation and the best ligands were subjected to a computational ADME-Tox properties prediction. After screening through molecular docking simulation, nine best compounds were identified to have a good interaction with EGFR protein according to its binding energy and RMSD value. The compounds were identified to form hydrogen bond interactions with the macromolecule. Two peptide compounds (PubChem ID: 20832941 and 9805315) have been predicted as the best ligands with desired pharmacological properties for the inhibition of EGFR tyrosine kinase.

Streptomyces lydicamycinicus sp. nov. and Its Secondary Metabolite Biosynthetic Gene Clusters for Polyketide and Nonribosomal Peptide Compounds.

(1) Background: Streptomyces sp. TP-A0598 derived from seawater produces lydicamycin and its congeners. We aimed to investigate its taxonomic status; (2) Methods: A polyphasic approach and whole genome analysis are employed; (3) Results: Strain TP-A0598 contained ll-diaminopimelic acid, glutamic acid, glycine, and alanine in its peptidoglycan. The predominant menaquinones were MK-9(H6) and MK-9(H8), and the major fatty acids were C16:0, iso-C15:0, iso-C16:0, and anteiso-C15:0. Streptomyces sp. TP-A0598 showed a 16S rDNA sequence similarity value of 99.93% (1 nucleottide difference) to Streptomyces angustmyceticus NRRL B-2347T. The digital DNA–DNA hybridisation value between Streptomyces sp. TP-A0598 and its closely related type strains was 25%–46%. Differences in phenotypic characteristics between Streptomyces sp. TP-A0598 and its phylogenetically closest relative, S. angustmyceticus NBRC 3934T, suggested strain TP-A0598 to be a novel species. Streptomyces sp. TP-A0598 and S. angustmyceticus NBRC 3934T harboured nine and 13 biosynthetic gene clusters for polyketides and nonribosomal peptides, respectively, among which only five clusters were shared between them, whereas the others are specific for each strain; and (4) Conclusions: For strain TP-A0598, the name Streptomyces lydicamycinicus sp. nov. is proposed; the type strain is TP-A0598T (=NBRC 110027T).

Quantitative structure–chromatographic retention relationship of synthesized peptides (HGRFG, NPNPT) and their derivatives

Carapax Trionycis extract peptides (HGRFG, NPNPT) are able to protect against CCl4-induced liver fibrosis. Therefore, this study applies to deal with chromatographic lipophilicity determination of synthesized peptides (HGRFG, NPNPT) and their derivatives using reversed-phase high performance liquid chromatography (RP-HPLC) combined with methanol-water mobile phase and two reversed-phase chromatographic columns (COSMOISL 5C18-MS-II and SHIMADZU-C18). The chromatographic lipophilicity of the analyzed compounds was expressed as logkw constant and correlated with lipophilicity descriptors. Quantitative structure-retention relationships (QSRR) analysis was performed to imitate chromatographic lipophilicity behavior using molecular descriptors. Modeling was performed using linear regression (LR) and multiple linear regression (MLR) methods with the help of principal component analysis (PCA) and hierarchical cluster analysis (HCA). The most influential molecular descriptors were lipophilicity descriptors, which are important for molecules ability to pass through biological membranes. All established QSRR models were statistically validated by standards, cross- and external validation parameters. According to these statistical validation parameters, MLR models (R2 > 0.856) were better for chromatographic lipophilicity prediction of peptide compounds. It can be concluded that chromatographic systems with COSMOISL 5C18-MS-II column were better for modeling of logkw than systems with SHIMADZU-C18 column. Modeling was performed in order to obtain lipophilicity profiles of investigated compounds as future drug candidates.

Contribution of TGF-β1 and Effects of Gene Silencer Pyrrole-Imidazole Polyamides Targeting TGF-β1 in Diabetic Nephropathy.

TGF-β1 has been known to induce diabetic nephropathy with renal fibrosis and glomerulosclerosis. DNA-recognized peptide compound pyrrole-imidazole (PI) polyamides as novel biomedicines can strongly bind promoter lesions of target genes to inhibit its transcription. We have developed PI polyamide targeting TGF-β1 for progressive renal diseases. In the present study, we evaluated the contribution of TGF-β1 in the pathogenesis of diabetic nephropathy, and examined the effects of PI polyamide targeting TGF-β1 on the progression of diabetic nephropathy in rats. For in vitro experiments, rat renal mesangial cells were incubated with a high (25 mM) glucose concentration. Diabetic nephropathy was established in vivo in eight-week-old Wistar rats by intravenously administering 60 mg/kg streptozotocin (STZ). We examined the effects of PI polyamide targeting TGF-β1 on phenotype and the growth of mesangial cells, in vitro, and the pathogenesis of diabetic nephropathy in vivo. High glucose significantly increased expression of TGF-β1 mRNA, changed the phenotype to synthetic, and increased growth of mesangial cells. STZ diabetic rats showed increases in urinary excretions of protein and albumin, glomerular and interstitial degenerations, and podocyte injury. Treatment with PI polyamide targeting TGF-β1 twice weekly for three months improved the glomerular and interstitial degenerations by histological evaluation. Treatment with PI polyamide improved podocyte injury by electron microscopy evaluation. These findings suggest that TGF-β1 may be a pivotal factor in the progression of diabetic nephropathy, and PI polyamide targeting TGF-β1 as a practical medicine may improve nephropathy.

Biodegradable electrospun patch containing cell adhesion or antimicrobial compounds for trachea repair in vivo

Difficulty breathing due to tracheal stenosis (i.e. narrowed airway) diminishes the quality of life and can potentially be life-threatening. Tracheal stenosis can be caused by congenital anomalies, external trauma, infection, intubation-related injury, and tumors. Common treatment methods for tracheal stenosis requiring surgical intervention include end-to-end anastomosis, slide tracheoplasty and/or laryngotracheal reconstruction. Although the current methods have demonstrated promise for treatment of tracheal stenosis, a clear need exists for the development of new biomaterials that can hold the trachea open after the stenosed region has been surgically opened, and that can support healing without the need to harvest autologous tissue from the patient. The current study therefore evaluated the use of electrospun nanofiber scaffolds encapsulating 3D-printed PCL rings to patch induced defects in rabbit tracheas. The nanofibers were a blend of polycaprolactone (PCL) and polylactide-co-caprolactone (PLCL), and encapsulated either the cell adhesion peptide, RGD, or antimicrobial compound, ceragenin-131 (CSA). Blank PCL/PLCL and PCL were employed as control groups. Electrospun patches were evaluated in a rabbit tracheal defect model for 12 weeks, which demonstrated re-epithelialization of the luminal side of the defect. No significant difference in lumen volume was observed for the PCL/PLCL patches compared to the uninjured positive control. Only the RGD group did not lead to a significant decrease in the minimum cross-sectional area compared to the uninjured positive control. CSA reduced bacteria growth in vitro, but did not add clear value in vivo. Adequate tissue in-growth into the patches and minimal tissue overgrowth was observed inside the patch material. Areas of future investigation include tuning the material degradation time to balance cell adhesion and structural integrity.

The In Vivo Effect of Transcellular Permeation Enhancers on the Intestinal Permeability of Two Peptide Drugs Enalaprilat and Hexarelin.

Permeation enhancers like sodium dodecyl sulfate (SDS) and caprate increase the intestinal permeability of small model peptide compounds, such as enalaprilat (349 Da). However, their effects remain to be investigated for larger low-permeability peptide drugs, such as hexarelin (887 Da). The objective of this single-pass perfusion study in rat was to investigate the effect of SDS at 5 mg/mL and of caprate administered at different luminal concentrations (5, 10, and 20 mg/mL) and pH (6.5 and 7.4). The small intestinal permeability of enalaprilat increased by 8- and 9-fold with SDS at 5 mg/mL and with caprate at 10 and 20 mg/mL but only at pH 7.4, where the free dissolved caprate concentration is higher than at pH 6.5 (5 vs. 2 mg/mL). Neither SDS nor caprate at any of the investigated luminal concentrations enhanced absorption of the larger peptide hexarelin. These results show that caprate requires doses above its saturation concentration (a reservoir suspension) to enhance absorption, most likely because dissolved caprate itself is rapidly absorbed. The absent effect on hexarelin may partly explain why the use of permeation enhancers for enabling oral peptide delivery has largely failed to evolve from in vitro evaluations into approved oral products. It is obvious that more innovative and effective drug delivery strategies are needed for this class of drugs.

Crystal structure of a tripeptide biphenyl hybrid C50H56N6O10·0.5H2O.

A peptide biphenyl hybrid compound {systematic name: dimethyl 2,2'-[((2S,2'S)-2,2'-{[(2S,2'S)-1,1'-([1,1'-biphen-yl]-2,2'-dicarbon-yl)bis-(pyrrolidine-1,2-diyl-2-carbon-yl)]bis-(aza-nedi-yl)}bis-(3-phenyl-propano-yl))bis-(aza-nedi-yl)](2S,2'S)-dipropionate hemihydrate}, C50H56N6O10·0.5H2O, was prepared by coupling of [1,1'-biphen-yl]-2,2'-dicarbonyl dichloride, tri-ethyl-amine and the tripeptide Pro-Phe-Ala in CH2Cl2 at 273 K under an N2 atmosphere. In the crystal, the asymmetric unit contains the peptide biphenyl hybrid accompanied by one-half of a water mol-ecule. A C atom of one of the proline rings is disordered between two positions in a 0.746 (11):0.254 (11) ratio. An important structural aspect of peptide compounds is their capacity to self-associate mediated by inter-molecular and intra-molecular hydrogen bonding. This characteristic can be useful in understanding the inter-actions between peptides and biomacromolecular targets, as well as to explain peptide properties.

The peptide compound urantide regulates collagen metabolism in atherosclerotic rat hearts and inhibits the JAK2/STAT3 pathway.

The aim of the present study was to investigate the effect of urantide on collagen metabolism in the hearts of rats with atherosclerosis (AS) by evaluating the expression of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway constituents. Urantide was delivered to rats with AS via tail vein injection for 3, 7 and 14 days. Serological indicators were identified by an automated biochemical analyzer. Histomorphological changes in the cardiac tissue of rats were observed by pathological staining techniques. The expression of genes and proteins was assessed using reverse transcription-quantitative PCR and western blot analysis, respectively. Localization of proteins was detected by immunofluorescence. Overexpression of urotensin II (UII) and its receptor, G protein-coupled receptor 14 (GPR14), was observed in the hearts of rats with AS and the expression of both proteins significantly declined after urantide administration. Triglyceride, total cholesterol, low-density lipoprotein, high-density lipoprotein and calcium levels were improved in rats with AS following treatment with urantide. Notably, urantide was able to antagonize the UII/GPR14 system. Urantide treatment resulted in markedly decreased expression levels of matrix metalloproteinase 2 (MMP-2), collagen type I/III, and genes and proteins in the JAK2/STAT3 pathway. By contrast, TIMP metallopeptidase inhibitor 2 (TIMP-2) levels were increased. In addition, the MMP-2/TIMP-2 protein ratio was significantly decreased in rats treated with urantide compared with AS rats with no urantide treatment. Constituents of the JAK2/STAT3 pathway and collagen type I/III were found to be localized in the diseased tissue and blood vessels of the hearts of rats with AS. In conclusion, urantide was able to effectively block the UII/GPR14 system by regulating the JAK2/STAT3 pathway and collagen metabolism. Inhibition of the UII/GPR14 system may prevent and potentially treat atherosclerotic myocardial fibrosis. Based on the current results, it was hypothesized that collagen metabolism may be associated with the JAK2/STAT3 pathway.

Highly Flexible Ligand Docking: Benchmarking of the DockThor Program on the LEADS-PEP Protein-Peptide Data Set.

Protein-peptide interactions play a crucial role in many cellular and biological functions, which justify the increasing interest in the development of peptide-based drugs. However, predicting experimental binding modes and affinities in protein-peptide docking remains a great challenge for most docking programs due to some particularities of this class of ligands, such as the high degree of flexibility. In this paper, we present the performance of the DockThor program on the LEADS-PEP data set, a benchmarking set composed of 53 diverse protein-peptide complexes with peptides ranging from 3 to 12 residues and with up to 51 rotatable bonds. The DockThor performance for pose prediction on redocking studies was compared with some state-of-the-art docking programs that were also evaluated on the LEADS-PEP data set, AutoDock, AutoDock Vina, Surflex, GOLD, Glide, rDock, and DINC, as well as with the task-specific docking protocol HPepDock. Our results indicate that DockThor could dock 40% of the cases with an overall backbone RMSD below 2.5 Å when the top-scored docking pose was considered, exhibiting similar results to Glide and outperforming other protein-ligand docking programs, whereas rDock and HPepDock achieved superior results. Assessing the docking poses closest to the crystal structure (i.e., best-RMSD pose), DockThor achieved a success rate of 60% in pose prediction. Due to the great overall performance of handling peptidic compounds, the DockThor program can be considered as suitable for docking highly flexible and challenging ligands, with up to 40 rotatable bonds. DockThor is freely available as a virtual screening Web server at https://www.dockthor.lncc.br/ .

Antibacterial activity of phytopathogenic Streptomyces strains against bacteria associated to clinical diseases

ABSTRACT: The genus Streptomyces is associated with the ability to produce and excrete a variety of bioactive compounds, such as antibiotic, antifungal and antiviral. Biological active polyketide and peptide compounds with applications in medicine, agriculture and biochemical research are synthesized by PKS-I and NRPS genes. The evaluation of the presence of these genes associated with the biosynthesis of secondary metabolites in different phytopathogenic Streptomyces strains were performed using degenerated primers. The positive signal was observed in 58/63 Streptomyces strains for NRPS gene, 43/63 for PKS-I, and for PKS-II all the 63 strains showed positive signal of amplification. These strains also were tested with double layer agar-well technique against bacterial with clinical importance, and it was possible to observe the Streptomyces spp. strains were able to inhibit the growth of 14, 20, 13 and 3 isolates Gram-positive and Gram-negative bacteria, Staphylococcus aureus (ATCC 25923), Bacillus cereus (ATCC 14579), Pseudomonas aeruginosa (ATCC 27853) and Escherichia coli (ATCC 11775) respectively. The Streptomyces sp. strains IBSBF 2019 and IBSBF 2397 showed antibacterial activity against all four bacteria-target tested.