| 30604885 |
Antimicrobial potential of haloalkaliphilic Nocardiopsis sp. AJ1 isolated from solar salterns in India |
10.1002/jobm.201800252. |
J Basic Microbiol |
Antimicrobial potential of haloalkaliphilic Nocardiopsis sp. AJ1 isolated from solar salterns in India
Abstract
- Antagonistic haloalkaliphilic Nocardiopsis sp. AJ1 (GenBank JX575136.1), isolated and identified from the saline soil of Kovalam solar salterns was able to produce antimicrobial secondary metabolites and effectively suppressed several bacterial and fungal pathogens. The metabolite extracted from ethyl acetate precipitation suppressed the bacterial and fungal pathogens to the range between 2.14 and 20.14 mm and also controlled the shrimp killer virus WSSV by 83% than the control and significantly (p < 0.05) differed. GC-MS analysis revealed that, the ethyl acetate precipitation contains pyrrolo (1,2-A(pyrazine-1,4-dione, hexahydro-3-(2-methylpropyl)-) and actinomycin C2. Non ribosomal peptide synthetase (NRPS) was amplified by PCR with the amplicon size of 750-800 bp length and further predicted the secondary structure by Iterative Threading Assembly Refinement (I-TASSER) bioinformatics approach. I-TASSER prediction helped to find out the secondary, 3-D structure, and ligand binding sites. The top ten modelling concluded that, the NRPS gene is closely similar to surfactin synthesizing gene, surfactin A synthetase C (SRFA-C). The findings revealed that, the active compounds from the secondary metabolites effectively suppressed the pathogenic bacteria, fungi, and virus and useful to develop antimicrobials.
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| 30658410 |
Mass Spectrometry Analysis and Biological Characterization of the Predatory Ant Odontomachus monticola Venom and Venom Sac Components |
10.3390/toxins11010050. |
Toxins (Basel) |
Mass Spectrometry Analysis and Biological Characterization of the Predatory Ant Odontomachus monticola Venom and Venom Sac Components
Abstract
- We previously identified 92 toxin-like peptides and proteins, including pilosulin-like peptides 1⁻6 from the predatory ant , by transcriptome analysis. Here, to further characterize venom components, we analyzed the venom and venom sac extract by ESI-MS/MS with or without trypsin digestion and reducing agent. As the low-molecular-mass components, we found amino acids (leucine/isoleucine, phenylalanine, and tryptophan) and biogenic amines (histamine and tyramine) in the venom and venom sac extract. As the higher molecular mass components, we found peptides and proteins such as pilosulin-like peptides, phospholipase A₂s, hyaluronidase, venom dipeptidyl peptidases, conotoxin-like peptide, and icarapin-like peptide. In addition to pilosulin-like peptides 1⁻6, we found three novel pilosulin-like peptides that were overlooked by transcriptome analysis. Moreover, pilosulin-like peptides 1⁻6 were chemically synthesized, and some of them displayed antimicrobial, hemolytic, and histamine-releasing activities.
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| 30673219 |
Discovery and Characterization of Cyclic and Acyclic Trypsin Inhibitors from Momordica dioica |
10.1021/acs.jnatprod.8b00716. |
J Nat Prod |
Discovery and Characterization of Cyclic and Acyclic Trypsin Inhibitors from Momordica dioica
Abstract
- Momordica trypsin inhibitors (TIs) such as those isolated from the seeds of the gấc fruit, Momordica cochinchinensis (MCoTI-I and MCoTI-II), are widely used as scaffolds for drug design studies. To more effectively exploit these molecules in the development of therapeutics, there is a need for wider discovery of the natural sequence diversity among TIs from other species in the Momordica subfamily. Here we report the discovery of the encoding gene and six TIs from the seeds of the spiny gourd, Momordica dioica, four of which possess novel sequences (Modi 1, 3, 5, and 6) and two (Modi 2 and 4) of which are known peptides (TI-14, TI-17) previously identified in Momordica subangulata. Modi 6 is an acyclic peptide featuring a pyrrolidone carboxylic acid modification, whereas the remaining five TIs are cyclic. All Modi peptides display similar overall structures and trypsin inhibitory activities. No toxicity was observed for these peptides when tested against cancer and insect cells. All Modi peptides were exceptionally stable over 24 h in human serum, indicating a dual strategy to stabilize the peptides in nature, either head-to-tail cyclization or N-pyrolation, which suggests these peptides might be excellent candidates as scaffolds for epitope stabilization in drug design studies.
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| 30681338 |
Singlet Oxygen Photooxidation of Peptidic Oxazoles and Thiazoles |
10.1021/acs.joc.8b02684. |
J Org Chem |
Singlet Oxygen Photooxidation of Peptidic Oxazoles and Thiazoles
Abstract
- Oxazoles and thiazoles are commonly found moieties in nonribosomal peptides (NRPs) and ribosomally synthesized post-translationally modified peptides (RiPPs), which are important biomolecules present in the environment and in natural waters. From previous studies, they seem susceptible to oxidation by singlet oxygen (O); therefore, we designed and synthesized model oxazole- and thiazole-peptides and measured their O bimolecular reaction rate constants, showing slow photooxidation under environmental conditions. We reasoned their stability through the electron-withdrawing effect of the carboxamide substituent. Reaction products were elucidated and support a reaction mechanism involving cycloaddition followed by a series of rearrangements. The first O bimolecular reaction rate constant for a RiPP, the thiazole-containing peptide Aerucyclamide A, was measured and found in good agreement with the model peptide's rate constant, highlighting the potential of using model peptides to study the transformations of other environmentally relevant NRPs and RiPPs.
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| 30687084 |
Conopeptides [V11L;V16D]ArIB and RgIA4: Powerful Tools for the Identification of Novel Nicotinic Acetylcholine Receptors in Monocytes |
10.3389/fphar.2018.01499. |
Front Pharmacol |
Conopeptides [V11L;V16D]ArIB and RgIA4: Powerful Tools for the Identification of Novel Nicotinic Acetylcholine Receptors in Monocytes
Abstract
- Venomous marine snails of the genus employ small peptides to capture prey, mainly osteichthyes, mollusks, and worms. A subset of these peptides known as α-conotoxins, are antagonists of nicotinic acetylcholine receptors (nAChRs). These disulfide-rich peptides provide a large number of evolutionarily refined templates that can be used to develop conopeptides that are highly selective for the various nAChR subtypes. Two such conopeptides, namely [V11L;V16D]ArIB and RgIA4, have been engineered to selectively target mammalian α7 and α9 nAChRs, respectively, and have been used to study the functional roles of these subtypes in immune cells. Unlike in neurons and cochlear hair cells, where α7 and α9 nAChRs, respectively, function as ligand-gated ion channels, in immune cells ligand-evoked ion currents have not been demonstrated. Instead, different metabotropic functions of α7 and α9 nAChRs have been described in monocytic cells including the inhibition of ATP-induced ion currents, inflammasome activation, and interleukin-1β (IL-1β) release. In addition to conventional nAChR agonists, diverse compounds containing a phosphocholine group inhibit monocytic IL-1β release and include dipalmitoyl phosphatidylcholine, palmitoyl lysophosphatidylcholine, glycerophosphocholine, phosphocholine, phosphocholine-decorated lipooligosaccharides from , synthetic phosphocholine-modified bovine serum albumin, and the phosphocholine-binding C-reactive protein. In monocytic cells, the effects of [V11L;V16D]ArIB and RgIA4 suggested that activation of nAChRs containing α9, α7, and/or α10 subunits inhibits ATP-induced IL-1β release. These results have been corroborated utilizing gene-deficient mice and small interfering RNA. Targeted re-engineering of native α-conotoxins has resulted in excellent tools for nAChR research as well as potential therapeutics. indicates possible presence of additional subunits.
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| 30714272 |
Mammalian antimicrobial peptide protegrin-4 self assembles and forms amyloid-like aggregates: Assessment of its functional relevance |
10.1002/psc.3151. |
J Pept Sci |
Mammalian antimicrobial peptide protegrin-4 self assembles and forms amyloid-like aggregates: Assessment of its functional relevance
Abstract
- Protegrin-4 (PG-4) is a member of the porcine leukocyte protegrins family of cysteine-rich antimicrobial peptides (AMPs) isolated from Sus scrofa. It consists of 18 amino acid residues and works as a part of innate immune system. In this study, we examined the intrinsic aggregation propensity of this AMP using multiple computational algorithms, namely, TANGO, AGGRESCAN, FOLDAMYLOID, AMYLPRED, and ZYGGREGATOR, and found that the peptide is predicted to have a high propensity for the β sheet formation that disposes this peptide to be amyloidogenic. Under in vitro conditions, PG-4 formed visible aggregates and displayed the hallmark properties of typical amyloids such as enhanced binding of Congo red, increased fluorescence with Thioflavin-T, and fibrillar morphology under transmission electron microscopy. Then we examined its antimicrobial activity against Bacillus subtilis and found that the aggregated peptide retained its antimicrobial activity. Additionally, the aggregates remain non-toxic to the HEK293 and Caco2 cells. Our study suggests that the inherent aggregation properties of AMP can rationally be explored as a potential source of peptide-based antimicrobials with enhanced stability.
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| 30753079 |
Total Synthesis and Configurational Revision of Mozamide A, a Hydroxy-Brunsvicamide |
10.1021/acs.joc.8b02836. |
J Org Chem |
Total Synthesis and Configurational Revision of Mozamide A, a Hydroxy-Brunsvicamide
Abstract
- The marine cyclopeptide mozamide A, a member of the class of anabaenopeptin-type peptides, was synthesized for the first time via a convergent and flexible route. The installation of the substituted tryptophan moieties was accomplished at the very end of the synthesis and thus allows easy modifications at this position. Comparison of the NMR data of the synthesized cyclopeptide with the natural product clearly indicates that the originally proposed structure of mozamide A cannot be correct. The synthesis of two other diastereomers allowed correction of the configuration of three amino acid building blocks. Mozamide A contains l-Val, d-Lys, and l-Ile (instead of d-Val, l-Lys, and l-allo-Ile) and is a hydroxylated brunsvicamide.
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| 30789695 |
Improving Selectivity, Proteolytic Stability, and Antitumor Activity of Hymenochirin-1B: A Novel Glycosylated Staple Strategy |
10.1021/acschembio.9b00046. |
ACS Chem Biol |
Improving Selectivity, Proteolytic Stability, and Antitumor Activity of Hymenochirin-1B: A Novel Glycosylated Staple Strategy
Abstract
- As a host defense peptide, hymenochirin-1B has attracted increasing attention for its strong cytotoxic activities. However, its poor selectivity and proteolytic stability remain major obstacles for clinical application. To solve these problems, we designed and synthesized a series of peptide analogues of hymenochirin-1B based on cationic residue substitution and stapling combined with a glycosylation strategy. Some analogues showed improvement not only in selectivity and proteolytic stability but also in antitumor activity. Among them, the glycosylated stapled peptide H-58 was identified as the most potential antitumor peptide. Flow cytometry and a competitive binding assay revealed that H-58 displayed significant antitumor selectivity. Confocal microscopy and nuclear staining with Hoechst dye demonstrated that H-58 entered the nucleus and caused DNA damage. In summary, the strategy of glycosylated stapled peptides is a promising approach for improving the antitumor selectivity, proteolytic stability, and antitumor activity of hymenochirin-1B, which can be used for other bioactive peptide modifications.
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| 30941386 |
Investigations of the key macrolactamisation step in the synthesis of cyclic tetrapeptide pseudoxylallemycin A |
10.1039/c9ob00227h. |
Org Biomol Chem |
Investigations of the key macrolactamisation step in the synthesis of cyclic tetrapeptide pseudoxylallemycin A
Abstract
- The total synthesis and structural confirmation of naturally occurring all l-cyclic tetrapeptide pseudoxylallemycin A is reported. X-ray crystallography revealed that the linear precursor adopted an all-trans (ttt) extended linear conformation, while its cyclic derivative adopts a trans,cis,trans,cis (tctc) conformation. Two kinetically favoured cyclic conformers prone to hydrolysis initially formed rapidly during cyclisation, with subsequent conversion to the thermodynamically stable tctc macrocycle taking place slowly. We postulate the initial unstable cyclic product undergoes an unprecedented nucleophilic ring opening with either the T3P or PyAOP by-products to give the linear ttt structure as a reactivated species and through a series of equilibria is slowly consumed by cyclisation to the thermodynamic product pseudoxylallemycin A. Consumption of the reactivated species by formation of pseudoxylallemycin A requires a trans-cis isomerism to occur and necessitates moderately increased reaction temperatures. Cyclisation with T3P was found to provide the greatest stereoretention. Synthesis and X-ray crystallography of the C-terminal epimer demonstrated its cyclisation to be kinetically favoured and to proceed without epimerisation despite also bearing an all-trans backbone.
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| 30975904 |
The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework |
10.1074/jbc.RA119.007491. |
J Biol Chem |
The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework
Abstract
- Venomous marine cone snails produce peptide toxins (conotoxins) that bind ion channels and receptors with high specificity and therefore are important pharmacological tools. Conotoxins contain conserved cysteine residues that form disulfide bonds that stabilize their structures. To gain structural insight into the large, yet poorly characterized conotoxin H-superfamily, we used NMR and CD spectroscopy along with MS-based analyses to investigate H-Vc7.2 from , a peptide with a VI/VII cysteine framework. This framework has Cys-Cys/Cys-Cys/Cys-Cys connectivities, which have invariably been associated with the inhibitor cystine knot (ICK) fold. However, the solution structure of recombinantly expressed and purified H-Vc7.2 revealed that although it displays the expected cysteine connectivities, H-Vc7.2 adopts a different fold consisting of two stacked β-hairpins with opposing β-strands connected by two parallel disulfide bonds, a structure homologous to the N-terminal region of the human granulin protein. Using structural comparisons, we subsequently identified several toxins and nontoxin proteins with this "mini-granulin" fold. These findings raise fundamental questions concerning sequence-structure relationships within peptides and proteins and the key determinants that specify a given fold.
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| 31056261 |
A significantly enhanced antibacterial spectrum of D-enantiomeric lipopeptide bactenecin |
10.1016/j.bbrc.2019.04.153. |
Biochem Biophys Res Commun |
A significantly enhanced antibacterial spectrum of D-enantiomeric lipopeptide bactenecin
Abstract
- Cationic antimicrobial peptides (CAMPs) are important antibiotics because they possess a broad spectrum of activity against both Gram-positive and Gram-negative bacteria, including those resistant to traditional antibiotics. The cyclic peptide bactenecin is a 12-amino acid CAMP that contains one intramolecular disulfide bond. To improve the antibacterial activity of bactenecin, we designed and synthesized several bactenecin analogs by applying multiple approaches, including amino acid substitution, use of the d-enantiomeric form, and lipidation. Among the synthetic analogs, d-enantiomeric bactenecin conjugated to capric acid, which we named dBacK-(cap), exhibited a significantly enhanced antibacterial spectrum with MIC values ranging from 1 to 8 μM against both Gram-positive and Gram-negative bacteria, including some drug-resistant bacteria. Upon exposure to dBacK-(cap), S. aureus cells were killed within 1 h at the MIC value, but full inactivation of E. coli required over 2 h. These results indicate that covalent addition of a d-amino acid and a fatty acid to bactenecin is the most effective approach for enhancing its antibacterial activity.
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| 31059155 |
Synthetic Lugdunin Analogues Reveal Essential Structural Motifs for Antimicrobial Action and Proton Translocation Capability |
10.1002/anie.201901589. |
Angew Chem Int Ed Engl |
Synthetic Lugdunin Analogues Reveal Essential Structural Motifs for Antimicrobial Action and Proton Translocation Capability
Abstract
- Lugdunin, a novel thiazolidine cyclopeptide, exhibits micromolar activity against methicillin-resistant Staphylococcus aureus (MRSA). For structure-activity relationship (SAR) studies, synthetic analogues obtained from alanine and stereo scanning as well as peptides with modified thiazolidine rings were tested for antimicrobial activity. The thiazolidine ring and the alternating d- and l-amino acid backbone are essential. Notably, the non-natural enantiomer displays equal activity, thus indicating the absence of a chiral target. The antibacterial activity strongly correlates with dissipation of the membrane potential in S. aureus. Lugdunin equalizes pH gradients in artificial membrane vesicles, thereby maintaining membrane integrity, which demonstrates that proton translocation is the mode of action (MoA). The incorporation of extra tryptophan or propargyl moieties further expands the diversity of this class of thiazolidine cyclopeptides.
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| 31063836 |
Pharmacokinetic characterization of kalata B1 and related therapeutics built on the cyclotide scaffold |
10.1016/j.ijpharm.2019.05.001. |
Int J Pharm |
Pharmacokinetic characterization of kalata B1 and related therapeutics built on the cyclotide scaffold
Abstract
- Oral activity has been described for cyclotide-containing traditional medicines, and demonstrated for reengineered cyclotides bearing grafted therapeutic epitopes, highlighting their potential for translation to the clinic. Here we report preclinical pharmacokinetic parameters for the prototypic cyclotide kalata B1 (kB1) and two orally active grafted analogues, ckb-KAL and ckb-KIN, to provide the first in vivo dose-exposure metrics for cyclotides. Native and grafted kB1 molecules exhibited multiple compartment kinetics and measurable but limited oral bioavailability of similar magnitude to several orally administered peptide drugs in the clinic. Cyclotides are mostly associated with the central compartment, and display small (0.07-0.13 L kg for kB1 and ckb-KIN) to moderate (1 L kg for ckb-KAL) steady state volumes of distribution. This study provides new data essential to the evaluation of cyclotides as therapeutics, validating them as a viable drug design scaffold with tunable pharmacokinetic properties.
|
| 31105871 |
Aplidin (plitidepsin) is a novel anti-myeloma agent with potent anti-resorptive activity mediated by direct effects on osteoclasts |
10.18632/oncotarget.26831. |
Oncotarget |
Aplidin (plitidepsin) is a novel anti-myeloma agent with potent anti-resorptive activity mediated by direct effects on osteoclasts
Abstract
- Despite recent progress in its treatment, Multiple Myeloma (MM) remains incurable and its associated bone disease persists even after complete remission. Thus, identification of new therapeutic agents that simultaneously suppress MM growth and protect bone is an unmet need. Herein, we examined the effects of Aplidin, a novel anti-cancer marine-derived compound, on MM and bone cells. In vitro, Aplidin potently inhibited MM cell growth and induced apoptosis, effects that were enhanced by dexamethasone (Dex) and bortezomib (Btz). Aplidin modestly reduced osteocyte/osteoblast viability and decreased osteoblast mineralization, effects that were enhanced by Dex and partially prevented by Btz. Further, Aplidin markedly decreased osteoclast precursor numbers and differentiation, and reduced mature osteoclast number and resorption activity. Moreover, Aplidin reduced Dex-induced osteoclast differentiation and further decreased osteoclast number when combined with Btz. Lastly, Aplidin alone, or suboptimal doses of Aplidin combined with Dex or Btz, decreased tumor growth and bone resorption in bone organ cultures that reproduce the 3D-organization and the cellular diversity of the MM/bone marrow niche. These results demonstrate that Aplidin has potent anti-myeloma and anti-resorptive properties, and enhances proteasome inhibitors blockade of MM growth and bone destruction.
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| 31134573 |
Building upon Nature's Framework: Overview of Key Strategies Toward Increasing Drug-Like Properties of Natural Product Cyclopeptides and Macrocycles |
10.1007/978-1-4939-9504-2_10. |
Methods Mol Biol |
Building upon Nature's Framework: Overview of Key Strategies Toward Increasing Drug-Like Properties of Natural Product Cyclopeptides and Macrocycles
Abstract
- The pharmaceutical industry has focused mainly in the development of small-molecule entities intended for oral administration for the past decades. As a result, the majority of existing drugs address only a narrow range of biological targets. In the era of post-genomics, transcriptomics, and proteomics, there is an increasing interest on larger modulators of proteins that can span larger surfaces, access new therapeutic mechanisms of action, and provide greater target specificity. Traditional drug-like molecules developed using "rule-of-five" (Ro5) guidelines have been proven ineffective against a variety of challenging targets, such as protein-protein interactions, nucleic acid complexes, and antibacterial modalities. However, natural products are known to be effective at modulating such targets, leading to a renewed focus by medicinal chemists on investigating underrepresented chemical scaffolds associated with natural products. Here we describe recent efforts toward identification of novel natural cyclopeptides and macrocycles as well as selected medicinal chemistry strategies to increase drug-like properties or further exploration of their activity.
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