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1.
BMC Microbiol ; 24(1): 193, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38831400

ABSTRACT

INTRODUCTION: Optimal exploitation of the huge amounts of agro-industrial residuals that are produced annually, which endangers the ecosystem and ultimately contributes to climate change, is one of the solutions available to produce value-added compounds. AIM AND OBJECTIVES: This study aimed at the economic production and optimization of surfactin. Therefore, the production was carried out by the microbial conversion of Potato Peel Waste (PPW) and Frying Oil Waste (FOW) utilizing locally isolated Bacillus halotolerans. Also, investigating its potential application as an antimicrobial agent towards some pathogenic strains. RESULTS: Screening the bacterial isolates for surfactin production revealed that the strain with the highest yield (49 g/100 g substrate) and efficient oil displacement activity was genetically identified as B. halotolerans. The production process was then optimized utilizing Central Composite Design (CCD) resulting in the amelioration of yield by 11.4% (from 49 to 55.3 g/100 g substrate) and surface tension (ST) by 8.3% (from 36 to 33 mN/m) with a constant level of the critical micelle concentration (CMC) at 125 mg/L. Moreover, the physiochemical characterization studies of the produced surfactin by FTIR, 1H NMR, and LC-MS/MS proved the existence of a cyclic lipopeptide (surfactin). The investigations further showed a strong emulsification affinity for soybean and motor oil (E24 = 50%), as well as the ability to maintain the emulsion stable over a wide pH (4-10) and temperature (10-100 °C) range. Interestingly, surfactin had a broad-spectrum range of inhibition activity against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, klebsiella pneumonia, and Candida albicans. CONCLUSION: Subsequently, the screening of the isolates and the utilized food-processing wastes along with the extraction technique resulted in a high yield of surfactin characterized by acceptable ST and CMC levels. However, optimization of the cultural conditions to improve the activity and productivity was achieved using Factor-At-A-Time (OFAT) and Central Composite Design (CCD). In contrast, surface activity recorded a maximum level of (33 mN/n) and productivity of 55.3 g/100 g substrate. The optimized surfactin had also the ability to maintain the stability of emulsions over a wide range of pH and temperature. Otherwise, the obtained results proved the promising efficiency of the surfactin against bacterial and fungal pathogens.


Subject(s)
Bacillus , Industrial Waste , Lipopeptides , Solanum tuberosum , Bacillus/metabolism , Bacillus/genetics , Bacillus/isolation & purification , Lipopeptides/pharmacology , Lipopeptides/metabolism , Lipopeptides/biosynthesis , Lipopeptides/chemistry , Lipopeptides/isolation & purification , Solanum tuberosum/microbiology , Peptides, Cyclic/pharmacology , Peptides, Cyclic/chemistry , Peptides, Cyclic/isolation & purification , Peptides, Cyclic/biosynthesis , Microbial Sensitivity Tests , Anti-Infective Agents/pharmacology , Anti-Infective Agents/metabolism , Anti-Infective Agents/chemistry , Anti-Infective Agents/isolation & purification , Agriculture/methods
2.
Org Lett ; 26(22): 4672-4677, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38787765

ABSTRACT

Picrachinentins A-F (1-6, respectively), six novel cyclopeptide alkaloid-type burpitides (CPABs), were isolated and fully elucidated from the EtOH extract of the stems and leaves of Picrasma chinensis. Structurally, compounds 1-6 have a 14-membered paracyclophane ring system that was closed through an ether bond between the ß-hydroxy amino acid and tyrosine and modified with a 4,5-methylenedioxybenzoyloxy (MDBz, 3 and 5) or hexanoyl (Hexa, 1, 2, 4, and 6) group at the N-terminus. Interestingly, this is the first report on the isolation and characterization of CPABs from plants of the Simaroubaceae family. In addition, all compounds showed a neuroprotective effect against H2O2-damaged SH-SY5Y cells. Compound 1 was further investigated for its neuroprotective activities using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease animal model, and it dramatically improved MPTP-impaired motor behavioral performance. Biochemical analysis revealed compound 1 restored the tyrosine hydroxylase expression in the striatum of the MPTP-damaged mouse brain, which demonstrates its protective effect on dopaminergic neurons.


Subject(s)
Alkaloids , Neuroprotective Agents , Peptides, Cyclic , Picrasma , Neuroprotective Agents/pharmacology , Neuroprotective Agents/chemistry , Neuroprotective Agents/isolation & purification , Animals , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Peptides, Cyclic/isolation & purification , Mice , Picrasma/chemistry , Alkaloids/pharmacology , Alkaloids/chemistry , Alkaloids/isolation & purification , Molecular Structure , Humans , Hydrogen Peroxide/pharmacology , Hydrogen Peroxide/antagonists & inhibitors , Plant Leaves/chemistry , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology
3.
J Nat Prod ; 87(4): 1230-1234, 2024 Apr 26.
Article in English | MEDLINE | ID: mdl-38626456

ABSTRACT

Three new cyclic heptapeptides, talaromides A-C (1-3), were isolated from cultures produced by the fungus Talaromyces siglerae (Ascomycota), isolated from an unidentified sponge. The structures, featuring an unusual proline-anthranilic moiety, were elucidated by analysis of spectroscopic data and chemical transformations, including the advanced Marfey's method and GITC derivatization. Talaromides A and B inhibited migration activity against PANC-1 human pancreatic cancer cells without significant cytotoxicity.


Subject(s)
Peptides, Cyclic , Porifera , Talaromyces , Talaromyces/chemistry , Animals , Porifera/microbiology , Humans , Molecular Structure , Peptides, Cyclic/pharmacology , Peptides, Cyclic/chemistry , Peptides, Cyclic/isolation & purification , Drug Screening Assays, Antitumor , Marine Biology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification
4.
Food Chem ; 449: 139243, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-38608605

ABSTRACT

Linusorbs (LO), cyclolinopeptides, are a group of cyclic hydrophobic peptides and considered a valuable by-product of flaxseed oil due to numerous health benefits. Currently applied acetone or methanol extraction could contaminate the feedstocks for further food-grade application. Using flaxseed cake as feedstock, this study established a practical method for preparing LO from pressed cake. Firstly, LO composition of 15 flaxseed cultivars was analyzed. Next, cold-pressed cake was milled and screened mechanically. The kernel and hull fractions were separated based on the disparity of their mechanical strength. Monitored by hyperspectral fluorescence, the LO-enriched kernel fraction separated from cold-pressed flaxseed cake was further used as feedstock for LO production. After ethanol extraction, partition, and precipitation, LOs were extracted from cold-pressed flaxseed cake with a purity of 91.4%. The proposed method could serve as feasible flaxseed cake valorization strategy and enable the preparation of other polar compounds such as flax lignan and mucilage.


Subject(s)
Flax , Peptides, Cyclic , Seeds , Flax/chemistry , Seeds/chemistry , Peptides, Cyclic/chemistry , Peptides, Cyclic/isolation & purification , Peptides, Cyclic/analysis , Food Handling , Plant Extracts/chemistry , Plant Extracts/isolation & purification
5.
Phytochemistry ; 222: 114074, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38604324

ABSTRACT

Ustiloxins I-M (1-5), five undescribed cyclopeptides bearing a 15-membered macrocyclic skeleton, were isolated from Cordyceps militaris. The structures of 1 and 5 were identified by spectroscopic and crystallographic methods, whereas the structures of 2-4 were assigned by spectroscopic and computational approaches. Biological evaluation of all the compounds toward human triple-negative breast cancer cells revealed that compounds 4 and 5 are toxic with IC50 values of 64.29 µM and 28.89 µM, respectively.


Subject(s)
Cordyceps , Peptides, Cyclic , Cordyceps/chemistry , Peptides, Cyclic/chemistry , Peptides, Cyclic/isolation & purification , Peptides, Cyclic/pharmacology , Humans , Molecular Structure , Drug Screening Assays, Antitumor , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Structure-Activity Relationship , Cell Proliferation/drug effects , Dose-Response Relationship, Drug
6.
J Antibiot (Tokyo) ; 77(6): 353-364, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38523145

ABSTRACT

The antimicrobial activity of tumescenamide C against the scab-forming S. scabiei NBRC13768 was confirmed with a potent IC50 value (1.5 µg/mL). Three tumescenamide C-resistant S. scabiei strains were generated to compare their gene variants. All three resistant strains contained nonsynonymous variants in genes related to cellobiose/cellotriose transport system components; cebF1, cebF2, and cebG2, which are responsible for the production of the phytotoxin thaxtomin A. Decrease in thaxtomin A production and the virulence of the three resistant strains were revealed by the LC/MS analysis and necrosis assay, respectively. Although the nonsynonymous variants were insufficient for identifying the molecular target of tumescenamide C, the cell wall component wall teichoic acid (WTA) was observed to bind significantly to tumescenamide C. Moreover, changes in the WTA contents were detected in the tumescenamide C-resistant strains. These results imply that tumescenamide C targets the cell wall system to exert antimicrobial effects on S. scabiei.


Subject(s)
Anti-Bacterial Agents , Depsipeptides , Peptides, Cyclic , Streptomyces , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Cell Wall/drug effects , Depsipeptides/pharmacology , Depsipeptides/chemistry , Depsipeptides/isolation & purification , Drug Resistance, Bacterial , Indoles , Microbial Sensitivity Tests , Peptides, Cyclic/pharmacology , Peptides, Cyclic/chemistry , Peptides, Cyclic/isolation & purification , Piperazines , Streptomyces/chemistry , Streptomyces/drug effects , Streptomyces/genetics , Teichoic Acids/metabolism
7.
J Nat Prod ; 85(11): 2641-2649, 2022 11 25.
Article in English | MEDLINE | ID: mdl-36282784

ABSTRACT

Two new antiplasmodial peptides, named koshidacins A (1) and B (2), were discovered from the culture broth of the Okinawan fungus Pochonia boninensis FKR-0564. Their structures, including absolute configurations, were elucidated by a combination of spectroscopic methods and chemical derivatization. Both compounds showed moderate in vitro antiplasmodial activity against Plasmodium falciparum strains, with IC50 values ranging from 17.1 to 0.83 µM. In addition, compound 2 suppressed 41% of malaria parasites in vivo when administered intraperitoneally at a dose of 30 mg/kg/day for 4 days.


Subject(s)
Antimalarials , Hypocreales , Peptides, Cyclic , Plasmodium falciparum , Antimalarials/chemistry , Antimalarials/isolation & purification , Antimalarials/pharmacology , Hypocreales/chemistry , Plasmodium falciparum/drug effects , Peptides, Cyclic/chemistry , Peptides, Cyclic/isolation & purification , Peptides, Cyclic/pharmacology
8.
J Nat Prod ; 85(5): 1256-1266, 2022 05 27.
Article in English | MEDLINE | ID: mdl-35438991

ABSTRACT

A metabolomics/peptidomics and genomics approach, using UPLC-MSE, molecular networking, and genome mining, was used to describe the serrawettin W2 lipopeptide family produced by Serratia marcescens NP2. Seven known serrawettin W2 analogues were structurally elucidated along with 17 new analogues, which varied based on the first (fatty acyl length of C8, C10, C12, or C12:1), fifth (Phe, Tyr, Trp, or Leu/Ile), and sixth (Leu, Ile, or Val) residues. Tandem MS results suggested that the previously classified serrawettin W3 may be an analogue of serrawettin W2, with a putative structure of cyclo(C10H18O2-Leu-Ser-Thr-Leu/Ile-Val). Chiral phase amino acid analysis enabled the distinction between l/d-Leu and l-Ile residues within nine purified compounds. 1H and 13C NMR analyses confirmed the structures of four purified new analogues. Additionally, genome mining was conducted using Serratia genome sequences available on the NCBI database to identify the swrA gene using the antiSMASH software. NRPSpredictor2 predicted the specificity score of the adenylation-domain within swrA with 100% for the first, second, and third modules (Leu-Ser-Thr), 60-70% for the fourth module (Phe/Trp/Tyr/Val), and 70% for the fifth module (Val/Leu/Ile), confirming MSE data. Finally, antibacterial activity was observed for compounds 6 and 11 against a clinical Enterococcus faecium strain.


Subject(s)
Lipopeptides , Peptides, Cyclic , Serratia marcescens , Amino Acid Sequence , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Chromatography, Liquid , Genomics , Lipopeptides/isolation & purification , Lipopeptides/metabolism , Lipopeptides/pharmacology , Lipoproteins , Metabolomics , Peptide Fragments , Peptides, Cyclic/isolation & purification , Peptides, Cyclic/pharmacology , Serratia marcescens/chemistry , Tandem Mass Spectrometry
9.
Mar Drugs ; 20(3)2022 Mar 20.
Article in English | MEDLINE | ID: mdl-35323515

ABSTRACT

Aspergillus is well-known as the second-largest contributor of fungal natural products. Based on NMR guided isolation, three nitrogen-containing secondary metabolites, including two new compounds, variotin B (1) and coniosulfide E (2), together with a known compound, unguisin A (3), were isolated from the ethyl acetate (EtOAc) extract of the deep-sea fungus Aspergillus unguis IV17-109. The planar structures of 1 and 2 were elucidated by an extensive analysis of their spectroscopic data (HRESIMS, 1D and 2D NMR). The absolute configuration of 2 was determined by comparison of its optical rotation value with those of the synthesized analogs. Compound 2 is a rare, naturally occurring substance with an unusual cysteinol moiety. Furthermore, 1 showed moderate anti-inflammatory activity with an IC50 value of 20.0 µM. These results revealed that Aspergillus unguis could produce structurally diverse nitrogenous secondary metabolites, which can be used for further studies to find anti-inflammatory leads.


Subject(s)
Anti-Inflammatory Agents , Aspergillus/chemistry , Biological Products , Peptides, Cyclic , Sulfides , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/metabolism , Aquatic Organisms , Aspergillus/metabolism , Biological Products/chemistry , Biological Products/isolation & purification , Biological Products/metabolism , Interleukin-6/metabolism , Lipopolysaccharides/pharmacology , Mice , Molecular Structure , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , Nitrogen/chemistry , Peptides, Cyclic/chemistry , Peptides, Cyclic/isolation & purification , Peptides, Cyclic/metabolism , Pyrrolidinones/chemistry , Pyrrolidinones/isolation & purification , Pyrrolidinones/metabolism , RAW 264.7 Cells , Secondary Metabolism , Sulfides/chemistry , Sulfides/isolation & purification , Sulfides/metabolism
10.
Mar Drugs ; 20(2)2022 Jan 21.
Article in English | MEDLINE | ID: mdl-35200623

ABSTRACT

Aeruginosamides (AEGs) are classified as cyanobactins, ribosomally synthesized peptides with post-translational modifications. They have been identified in cyanobacteria of genera Microcystis, Oscillatoria, and Limnoraphis. In this work, the new data on the in vitro activities of three AEG variants, AEG A, AEG625 and AEG657, and their interactions with metabolic enzymes are reported. Two aeruginosamides, AEG625 and AEG657, decreased the viability of human breast cancer cell line T47D, but neither of the peptides was active against human liver cancer cell line Huh7. AEGs also did not change the expression of MIR92b-3p, but for AEG625, the induction of oxidative stress was observed. In the presence of a liver S9 fraction containing microsomal and cytosolic enzymes, AEG625 and AEG657 showed high stability. In the same assays, quick removal of AEG A was recorded. The peptides had mild activity against three cytochrome P450 enzymes, CYP2C9, CYP2D6 and CYP3A4, but only at the highest concentration used in the study (60 µM). The properties of AEGs, i.e., cytotoxic activity and in vitro interactions with important metabolic enzymes, form a good basis for further studies on their pharmacological potential.


Subject(s)
Antineoplastic Agents/pharmacology , Cyanobacteria/metabolism , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Peptides, Cyclic/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cytochrome P-450 Enzyme Inhibitors/chemistry , Cytochrome P-450 Enzyme Inhibitors/isolation & purification , Humans , Liver Neoplasms/drug therapy , Oxidative Stress/drug effects , Peptides, Cyclic/chemistry , Peptides, Cyclic/isolation & purification
11.
Fitoterapia ; 156: 105072, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34728327

ABSTRACT

Pseudostellaria heterophylla (Miq.) Pax. (Taizishen, TZS) contains a variety of natural active cyclic-peptide compounds (CP). In this article, four kinds of CP monomers were isolated by HPLC and the structures were identified by mass spectrometry. The in vivo absorption of CP was detected by UPLC-MS/MS. The interaction between CP and membrane receptor was analyzed by SPR. As a result, the relative absorption rate of CP was Pesudostellarin B > Heterophyllin B > Pesudostellarin C > Pesudostellarin E. The difference in absorption rate of CP in vivo was related to its interaction with membrane receptors. The absorption mechanism of CP might be different. This is the first report that in vivo absorption study of different CP from TZS and explore its absorption mechanism, laying a theoretical foundation for the research and development of its oral drugs, and providing new ideas for the study of the absorption mechanism of CP from traditional Chinese medicine.


Subject(s)
Caryophyllaceae/chemistry , Peptides, Cyclic/metabolism , Animals , Chromatography, High Pressure Liquid , Male , Mass Spectrometry , Peptides, Cyclic/chemistry , Peptides, Cyclic/isolation & purification , Rats
12.
Protein Expr Purif ; 191: 106026, 2022 03.
Article in English | MEDLINE | ID: mdl-34838724

ABSTRACT

Small and medium-sized peptides are gaining popularity in biomedical applications, including therapeutic target development. As an alternative to chemical synthesis, we describe a complete pipeline for the production of linear as well as structurally constrained cyclic peptides in an E. coli expression system in this study. A plasmid vector containing a novel N terminal HOE tag (28 amino acids in length) that fuses with the peptide was created. The HOE tag contains sites for both chemical (CNBr) and enzymatic (enterokinase) cleavage, making it easy to isolate the peptide after production. A total of 21 peptides (17 cyclic and 4 linear) were synthesized, and the HOE tag was successfully removed using either CNBr (9 peptides) or enterokinase (12 peptides). The presence of a disulfide bond was confirmed in six representative cyclic peptides. In this study we have provided detailed instructions on primers design strategy, overexpression and purification of HOE tagged peptides, chemical and enzymatic cleavage, and confirmation of the cyclic form of peptides. We are confident that this pipeline will assist researchers in producing multiple recombinant peptides in a cost-effective and time-efficient manner.


Subject(s)
Escherichia coli , Gene Expression , Peptides, Cyclic , Escherichia coli/chemistry , Escherichia coli/genetics , Escherichia coli/metabolism , Peptides, Cyclic/biosynthesis , Peptides, Cyclic/chemistry , Peptides, Cyclic/genetics , Peptides, Cyclic/isolation & purification
13.
J Nat Prod ; 84(11): 2914-2922, 2021 11 26.
Article in English | MEDLINE | ID: mdl-34672199

ABSTRACT

Plants are an excellent source of bioactive peptides, often with disulfide bonds and/or a cyclic backbone. While focus has predominantly been directed at disulfide-rich peptides, a large family of small, cyclic plant peptides lacking disulfide bonds, known as orbitides, has been relatively ignored. A recently discovered subfamily of orbitides is the PawL-derived peptides (PLPs), produced during the maturation of precursors for seed storage albumins. Although their evolutionary origins have been dated, in-depth exploration of the family's structural characteristics and potential bioactivities remains to be conducted. Here we present an extensive and systematic characterization of the PLP family. Nine PLPs were chosen and prepared by solid phase peptide synthesis. Their structural features were studied using solution NMR spectroscopy, and seven were found to possess regions of backbone order. Ordered regions consist of ß-turns, with some PLPs adopting two well-defined ß-turns within sequences as short as seven residues, which are largely the result of side chain interactions. Our data highlight that the sequence diversity within this family results in equally diverse structures. None of these nine PLPs showed antibacterial or antifungal activity.


Subject(s)
Peptides, Cyclic/chemistry , Anti-Infective Agents/pharmacology , Magnetic Resonance Spectroscopy , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/isolation & purification , Peptides, Cyclic/pharmacology , Solid-Phase Synthesis Techniques
14.
J Mol Model ; 27(11): 314, 2021 Oct 08.
Article in English | MEDLINE | ID: mdl-34623510

ABSTRACT

An integrated molecular modeling protocol resulting from the combination of conceptual density functional theory (CDFT) chemical reactivity descriptors with several chemoinformatics tools has been used for the study of the chemical reactivity and bioactivity properties of a group of marine cyclic peptides. CP-CDFT is a branch of computational chemistry and molecular modeling dedicated to the study of peptides. The protocol allowed the estimation of the CDFT-based reactivity indices together with the associated physicochemical parameters that can help to identify the ability of the studied peptides to behave as potential useful drugs. This was complemented with an analysis of the bioactivity and pharmacokinetics parameters related to the ADMET (absorption, distribution, metabolism, excretion, and toxicity) features. Some examples related to the ability of the CDFT-based chemical reactivity descriptors for the prediction of the pKas of the peptides as well as their potential as AGE inhibitors are also presented.


Subject(s)
Aquatic Organisms/chemistry , Cheminformatics/methods , Drug Evaluation, Preclinical , Peptides, Cyclic/chemistry , Aquatic Organisms/isolation & purification , Density Functional Theory , Models, Molecular , Molecular Structure , Peptides, Cyclic/isolation & purification
15.
J Nat Prod ; 84(8): 2249-2255, 2021 08 27.
Article in English | MEDLINE | ID: mdl-34387477

ABSTRACT

Acremonamide (1) was isolated from a marine-derived fungus belonging to the genus Acremonium. The chemical structure of 1 was established using MS, UV, and NMR spectroscopic data analyses. Acremonamide (1) was found to contain N-Me-Phe, N-Me-Ala, Val, Phe, and 2-hydroxyisovaleric acid. The absolute configurations of the four aforementioned amino acids were determined through acid hydrolysis followed by the advanced Marfey's method, whereas the absolute configuration of 2-hydroxyisovaleric acid was determined through GC-MS analysis after formation of the O-pentafluoropropionylated derivative of the (-)-menthyl ester of 2-hydroxyisovaleric acid. As an intrinsic biological activity, acremonamide (1) did not exert cytotoxicity to cancer and noncancer cells and increased the migration and invasion. Based on these activities, the wound healing properties of acremonamide (1) were confirmed in vitro and in vivo.


Subject(s)
Acremonium/chemistry , Peptides, Cyclic/pharmacology , Wound Healing/drug effects , Animals , Aquatic Organisms/chemistry , Caco-2 Cells , HaCaT Cells , Humans , Male , Mice , Mice, Inbred BALB C , Molecular Structure , NIH 3T3 Cells , Peptides, Cyclic/isolation & purification
16.
Cancer Sci ; 112(10): 4335-4345, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34387029

ABSTRACT

Kita-kyushu lung cancer antigen 1 (KK-LC-1) is a kind of cancer-testis antigen with anti-tumor potential for clinical application. As a class of small-molecule antigen conjugate, tumor-targeting peptides have broad application prospects in gastric cancer diagnosis, imaging, and biological treatment. Here, we screened specific cyclic nonapeptides from a phage-display library. The targeting peptide with the best affinity was selected and further verified in ex vivo tissue sections. Finally, enrichment of targeting peptides in tumor tissues was observed in vivo, and the dynamic biodistribution process was also observed with micro-positron emission tomography (micro-PET)/computed tomography (CT) imaging. Studies showed that the specific cyclic nonapeptide had a high binding capacity for KK-LC-1 protein. It has a strong affinity and specificity for KK-LC-1-expressing positive tumor cells. Targeting peptides were significantly enriched at tumor sites in vivo, with very low normal tissue background. These findings demonstrated that the KK-LC-1 targeting peptide has high clinical potential.


Subject(s)
Antigens, Neoplasm/metabolism , Bacteriophages/chemistry , Peptide Library , Peptides, Cyclic/metabolism , Stomach Neoplasms/metabolism , Animals , Bacteriophages/genetics , Cell Line, Tumor , Epitopes/metabolism , Humans , Mice , Molecular Targeted Therapy , Organ Specificity , Peptides, Cyclic/chemistry , Peptides, Cyclic/isolation & purification , Sequence Analysis, DNA/methods , Stomach Neoplasms/therapy , Tissue Distribution
17.
Pharm Biol ; 59(1): 933-936, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34236286

ABSTRACT

CONTEXT: Streptomyces species are prolific sources of bioactive secondary metabolites known especially for their antimicrobial and anticancer activities. OBJECTIVE: This study sought to isolate and characterize antioxidant molecules biosynthesized by Streptomyces sp. KTM18. The antioxidant potential of an isolated compound and its toxicity were accessed. MATERIALS AND METHODS: The compound was purified using bioassay-guided chromatography techniques. Nuclear magnetic resonance (NMR) experiments were carried out for structure elucidation. The antioxidant potential of the isolated compound was determined using DPPH free radical scavenging assay. The toxicity of the isolated compound was measured using a brine shrimp lethality (BSL) assay. RESULTS: Ethyl acetate extract of Streptomyces sp. KTM18 showed more than 90% inhibition of DPPH free radical at 50 µg/mL of the test concentration. These data were the strongest among 13 Streptomyces isolates (KTM12-KTM24). The active molecule was isolated and characterized as maculosin (molecular formula, C14H16N2O3 as determined by the [M + H]+ peak at 261.1259). The DPPH free radical scavenging activity of pure maculosin was higher (IC50, 2.16 ± 0.05 µg/mL) than that of commercial butylated hydroxyanisole (BHA) (IC50, 4.8 ± 0.05 µg/mL). No toxicity was observed for maculosin (LD50, <128 µg/mL) in brine shrimp lethality assay (BSLA) up to the compound's antioxidant activity (IC50) concentration range. The commercial standard, berberine chloride, showed toxicity in BSLA with an LD50 value of 8.63 ± 0.15 µg/mL. CONCLUSIONS: Maculosin may be a leading drug candidate in various cosmetic and therapeutic applications owing to its strong antioxidant and non-toxic properties.


Subject(s)
Antioxidants/pharmacology , Free Radical Scavengers/pharmacology , Peptides, Cyclic/pharmacology , Piperazines/pharmacology , Streptomyces/metabolism , Animals , Antioxidants/isolation & purification , Antioxidants/toxicity , Artemia , Biphenyl Compounds , Free Radical Scavengers/isolation & purification , Free Radical Scavengers/toxicity , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Peptides, Cyclic/isolation & purification , Peptides, Cyclic/toxicity , Picrates , Piperazines/isolation & purification , Piperazines/toxicity , Secondary Metabolism , Toxicity Tests
18.
J Nat Prod ; 84(7): 2028-2034, 2021 07 23.
Article in English | MEDLINE | ID: mdl-34191504

ABSTRACT

The genus Sphaerostilbella comprises fungi that colonize basidiomata of wood-inhabiting fungi, including important forest pathogens. Studies of fermentation cultures of an isolate (TFC201724) collected on the foothills of Himalayas, and closely related to S. broomeana isolates from Europe, led to the identification of a new cyclic octapeptide along with two closely related analogues (1-3) and four dioxopiperazines (4-7). The structure of the lead compound, broomeanamide A (1), was assigned mainly by analysis of 2D NMR and HRESIMS data. The structure consisted of one unit each of N-MeVal, Ala, N-MePhe, Pro, Val, and Ile and two N-MeLeu units. The amino acid sequence was determined on the basis of 2D NMR and HRESIMSMS data. NMR and HRMS data revealed that the other two new peptides have the same amino acid composition except that the Ile unit was replaced with Val in one instance (2) and the N-MeVal unit was replaced with Val in the other (3). The absolute configuration of 1 was assigned by analysis of the acid hydrolysate by application of Marfey's method using both C18 and C3 bonded-phase columns. Broomeanamide A (1) showed antifungal activity against Cryptococcus neoformans and Candida albicans, with MIC values of 8.0 and 64 µg/mL, respectively.


Subject(s)
Antifungal Agents/pharmacology , Hypocreales/chemistry , Peptides, Cyclic/pharmacology , Amino Acid Sequence , Antifungal Agents/isolation & purification , Candida albicans/drug effects , Cryptococcus neoformans/drug effects , India , Molecular Structure , Peptides, Cyclic/isolation & purification
19.
J Pept Sci ; 27(8): e3326, 2021 Aug.
Article in English | MEDLINE | ID: mdl-33960079

ABSTRACT

The goji berry is widely used as tonics; however, the antihuman cervical carcinoma effect and underlying mechanism of goji berry peptide remain to be elucidated. The cyclic peptides are appealing targets in antitumor agent development, and in current study, three novel goji berry cyclic peptides (GCPs) were isolated and amino acid sequence identified. Among them, GCP-1 (Cycle-(Trp-Glu-His-Thr)) inhibited proliferation and induced human cervical cancer (HeLa) cells apoptosis and blocked the HeLa cells in G0/G1 phase significantly. Furthermore, the GCP-1 also inhibited the cervical carcinoma growth in vivo. Moreover, GCP-1 suppressed the cyclin expression and activated the caspase cascade and poly(ADP-ribose) polymerase. Of note, GCP-1 may be a promising novel inhibitor of human cervical cancer.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Lycium/chemistry , Peptides, Cyclic/pharmacology , Uterine Cervical Neoplasms/drug therapy , Amino Acid Sequence , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Apoptosis/drug effects , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Female , HeLa Cells , Humans , Mice , Mice, Inbred BALB C , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Peptides, Cyclic/chemistry , Peptides, Cyclic/isolation & purification , Uterine Cervical Neoplasms/pathology
20.
J Med Chem ; 64(11): 7422-7433, 2021 06 10.
Article in English | MEDLINE | ID: mdl-34048659

ABSTRACT

Neurotoxic aggregation of ß-amyloid (Aß) peptides is a hallmark of Alzheimer's disease and increased reactive oxygen species (ROS) is an associated process. In the present study, we report the neuroprotective effects of disulfide-rich, circular peptides from Clitoria ternatea (C. ternatea) (butterfly pea) on Aß-induced toxicity in transgenic Caenorhabditis elegans. Cyclotides (∼30 amino acids long) are a special class of cyclic cysteine knot peptides. We show that cyclotide-rich fractions from different plant tissues delay Aß-induced paralysis in the transgenic CL4176 strain expressing the human muscle-specific Aß1-42 gene. They also improved Aß-induced chemotaxis defects in CL2355 strain expressing Aß1-42 in the neuronal cells. ROS assay suggests that this protection is likely mediated by the inhibition of Aß oligomerization. Furthermore, Aß deposits were reduced in the CL2006 strain treated with the fractions. The study shows that cyclotides from C. ternatea could be a source of a novel pharmacophore scaffold against neurodegenerative diseases.


Subject(s)
Amyloid beta-Peptides/metabolism , Caenorhabditis elegans/metabolism , Clitoria/metabolism , Disulfides/chemistry , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Peptide Fragments/metabolism , Peptides, Cyclic/chemistry , Amino Acid Sequence , Amyloid beta-Peptides/genetics , Animals , Animals, Genetically Modified/metabolism , Animals, Genetically Modified/physiology , Caenorhabditis elegans/physiology , Chemotaxis/drug effects , Chromatography, High Pressure Liquid , Neuroprotective Agents/chemistry , Neuroprotective Agents/isolation & purification , Neuroprotective Agents/therapeutic use , Paralysis/drug therapy , Paralysis/pathology , Peptide Fragments/genetics , Peptides, Cyclic/isolation & purification , Peptides, Cyclic/pharmacology , Peptides, Cyclic/therapeutic use , Reactive Oxygen Species/metabolism , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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