Identification of protegrin-1 as a stable and nontoxic scaffold among protegrin family - a computational approach.
01 Jun 2019-Journal of Biomolecular Structure & Dynamics (Taylor & Francis)-Vol. 37, Iss: 9, pp 2430-2439
TL;DR: The authors claim the superiority of PG1 as a nontoxic stable scaffold among its family, for future therapeutic peptide analogs.
Abstract: Achieving both, nontoxicity and stability in antimicrobial peptides (AMP) is a challenge. This study predicts a structurally stable, nontoxic scaffold among the protegrin family, for future therapeutic peptide analogs. Protegrins (PG) are a class of pharmaceutically approved, in demand AMPs, which require further improvement in terms of nontoxicity and stability. Out of five protegrins viz., PG1, PG2, PG3, PG4 and PG5, PG1 has been predicted as best scaffold. Prediction was based upon sequential elimination of other protegrins, using computational methods to assess the extracellular bacterial membrane penetrability, nontoxicity and structural stability by geometric observables. Initially, PG2 and PG4 showing the lowest membrane penetrability and highest toxicity respectively, were screened out. Among the remaining three protegrins, PG1 displayed both lowest root mean square deviation and radius of gyration, with a considerable occupancy of seven H-bonds and established uniform secondary structure profile throughout its ensembles. Therefore, the authors claim the superiority of PG1 as a nontoxic stable scaffold among its family. Communicated by Ramaswamy H. Sarma.
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TL;DR: This review summarizes the natural sources, structures, modes of action, and applications of microbial peptides in the food and pharmaceutical industries and suggests their applications in food, medicine, agriculture, animal husbandry, and aquaculture.
Abstract: Antimicrobial peptides (AMPs) are constituents of the innate immune system in every kind of living organism. They can act by disrupting the microbial membrane or without affecting membrane stability. Interest in these small peptides stems from the fear of antibiotics and the emergence of microorganisms resistant to antibiotics. Through membrane or metabolic disruption, they defend an organism against invading bacteria, viruses, protozoa, and fungi. High efficacy and specificity, low drug interaction and toxicity, thermostability, solubility in water, and biological diversity suggest their applications in food, medicine, agriculture, animal husbandry, and aquaculture. Nanocarriers can be used to protect, deliver, and improve their bioavailability effectiveness. High cost of production could limit their use. This review summarizes the natural sources, structures, modes of action, and applications of microbial peptides in the food and pharmaceutical industries. Any restrictions on AMPs’ large-scale production are also taken into consideration.
10 citations
TL;DR: This review paper presents a comprehensive overview of biological roles, lytic mechanism of action and applications of PG-1, thus providing a thorough understanding of this β-sheet peptide, which structurally resembles defensin peptides.
Abstract: Multi drug resistance is a major problem of the twenty first century. In order to combat this issue, there is an urgent need in the pharmaceutical industry, for novel therapeutic agents. Antimicrobial peptides such as protegrins which exhibit non-specific membranolytic action can be viewed as probable therapeutic agents and replace conventional antibiotics. Protegrin-1 (PG-1) is a peptide isolated from porcine leucocytes. Its primary role is its antimicrobial activity against a broad-spectrum of gram-positive as well as gram-negative bacteria and fungi. Its antagonistic activity can be accounted by its pore formation mechanism in microbial membranes. In addition, PG-1 has multiple roles viz., anticancer and antiviral activity, immunomodulatory functions and numerous applications which increase its suitability as a potential therapeutic agent. This review paper presents a comprehensive overview of biological roles, lytic mechanism of action and applications of PG-1, thus providing a thorough understanding of this β-sheet peptide, which structurally resembles defensin peptides.
9 citations
Cites background from "Identification of protegrin-1 as a ..."
...PG-1 was identified as a promising therapeutic scaffold among its peptide family based on computational techniques such as interaction with representative gram-negative 1 3 bacterial membrane, mammalian cell toxicity and staticdynamic structural stability (Shruti and Rajasekaran 2019)....
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...1 3 bacterial membrane, mammalian cell toxicity and staticdynamic structural stability (Shruti and Rajasekaran 2019)....
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TL;DR: In this article, the role of antimicrobial peptides in the development and maturation of ovarian follicles was investigated, and it was shown that PG-1 is associated with increased expression of cell-cycle progression-related genes such as cyclin D1(CCND1), cyclin CND2 (CCND2), and cyclin B1 (CCNB1).
Abstract: Antimicrobial peptides (AMPs) are traditionally known to be essential components in host defense via their broad activities against bacteria, fungi, viruses, and protozoa. Their immunomodulatory properties have also recently received considerable attention in mammalian somatic tissues of various species. However, little is known regarding the role of AMPs in the development and maturation of ovarian follicles. Protegrin-1 (PG-1) is an antimicrobial peptide which is known to have potent antimicrobial activity against both gram positive and negative bacteria. Here we report that the PG-1 is present in the porcine ovarian follicular fluid. Treatment of granulosa cell with PG-1 enhanced granulosa cell proliferation in a dose-dependent manner. This is accompanied by increased expression of cell-cycle progression-related genes such as cyclin D1(CCND1), cyclin D2 (CCND2), and cyclin B1(CCNB1). Additionally, Western blot analysis showed that PG-1 increased phosphorylated epidermal growth factor receptor (EGFR), and the phosphorylated-/total extracellular signal-regulated kinase (ERK)1/2 ratio. Pretreatment with either U0126, a specific ERK1/2 phosphorylation inhibitor, or EGFR kinase inhibitor, AG1478, blocked the PG-1 induced proliferation. Moreover, luciferase reporter assay revealed that ETS domain-containing protein-1 (Elk1) C/EBP homologous protein (CHOP), and the transcription activators downstream of the MAPK pathway, were activated by PG-1. These data collectively suggest that PG-1 may regulate pig granulosa cell proliferation via EGFR-MAPK pathway., Hence, our finding offers insights into the role of antimicrobial peptides on follicular development regulation.
4 citations
TL;DR: In this article , a comparative study of intermolecular interactions between SARS-CoV-2 spike protein S1 and AMPs was performed relative to S1-ACE2p interactions.
Abstract: In COVID-19 infection, the SARS-CoV-2 spike protein S1 interacts to the ACE2 receptor of human host, instigating the viral infection. To examine the competitive inhibitor efficacy of broad spectrum alpha helical AMPs extracted from frog skin, a comparative study of intermolecular interactions between viral S1 and AMPs was performed relative to S1-ACE2p interactions. The ACE2 binding region with S1 was extracted as ACE2p from the complex for ease of computation. Surprisingly, the Spike-Dermaseptin-S9 complex had more intermolecular interactions than the other peptide complexes and importantly, the S1-ACE2p complex. We observed how atomic displacements in docked complexes impacted structural integrity of a receptor-binding domain in S1 through conformational sampling analysis. Notably, this geometry-based sampling approach confers the robust interactions that endure in S1-Dermaseptin-S9 complex, demonstrating its conformational transition. Additionally, QM calculations revealed that the global hardness to resist chemical perturbations was found more in Dermaseptin-S9 compared to ACE2p. Moreover, the conventional MD through PCA and the torsional angle analyses indicated that Dermaseptin-S9 altered the conformations of S1 considerably. Our analysis further revealed the high structural stability of S1-Dermaseptin-S9 complex and particularly, the trajectory analysis of the secondary structural elements established the alpha helical conformations to be retained in S1-Dermaseptin-S9 complex, as substantiated by SMD results. In conclusion, the functional dynamics proved to be significant for viral Spike S1 and Dermaseptin-S9 peptide when compared to ACE2p complex. Hence, Dermaseptin-S9 peptide inhibitor could be a strong candidate for therapeutic scaffold to prevent infection of SARS-CoV-2.
3 citations
References
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TL;DR: VMD is a molecular graphics program designed for the display and analysis of molecular assemblies, in particular biopolymers such as proteins and nucleic acids, which can simultaneously display any number of structures using a wide variety of rendering styles and coloring methods.
46,130 citations
"Identification of protegrin-1 as a ..." refers methods in this paper
...The ensembles for all protegrins were further subjected to determination of secondary structure profile in VMD software (Humphrey et al., 1996)....
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TL;DR: Two unusual extensions are presented: Multiscale, which adds the ability to visualize large‐scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales.
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35,698 citations
"Identification of protegrin-1 as a ..." refers methods in this paper
...Therefore, the number and distance (Å) of Hbonds were calculated, using UCSF Chimera software (Pettersen et al., 2004) which considered and displayed Hbonds within 2.5 Å. Generation of protegrin conformers and analysis of structural parameters Evaluation of static protegrin model data was…...
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TL;DR: The goals of the PDB are described, the systems in place for data deposition and access, how to obtain further information and plans for the future development of the resource are described.
Abstract: The Protein Data Bank (PDB; http://www.rcsb.org/pdb/ ) is the single worldwide archive of structural data of biological macromolecules. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.
34,239 citations
"Identification of protegrin-1 as a ..." refers methods in this paper
..., 1ZY6, 2MUH, 2MZ6 and 2NC7 were retrieved from PDB database (Berman et al., 2000)....
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TL;DR: A new program called Clustal Omega is described, which can align virtually any number of protein sequences quickly and that delivers accurate alignments, and which outperforms other packages in terms of execution time and quality.
Abstract: Multiple sequence alignments are fundamental to many sequence analysis methods. Most alignments are computed using the progressive alignment heuristic. These methods are starting to become a bottleneck in some analysis pipelines when faced with data sets of the size of many thousands of sequences. Some methods allow computation of larger data sets while sacrificing quality, and others produce high-quality alignments, but scale badly with the number of sequences. In this paper, we describe a new program called Clustal Omega, which can align virtually any number of protein sequences quickly and that delivers accurate alignments. The accuracy of the package on smaller test cases is similar to that of the high-quality aligners. On larger data sets, Clustal Omega outperforms other packages in terms of execution time and quality. Clustal Omega also has powerful features for adding sequences to and exploiting information in existing alignments, making use of the vast amount of precomputed information in public databases like Pfam.
12,489 citations
"Identification of protegrin-1 as a ..." refers methods in this paper
...To aid the process of identification of a suitable protegrin template for modelling PG4, multiple sequence alignment for the primary sequences of protegrins, PG1, PG2, PG3, PG4 and PG5 was performed, using Clustal Omega (Sievers et al., 2011)....
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...Then, similarity scores for all protegrins were calculated, using Gonnet PAM 250 matrices in Clustal Omega....
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TL;DR: An environment for comparative protein modeling is developed that consists of SWISS‐MODEL, a server for automated comparativeprotein modeling and of the SWiss‐PdbViewer, a sequence to structure workbench that provides a large selection of structure analysis and display tools.
Abstract: Comparative protein modeling is increasingly gaining interest since it is of great assistance during the rational design of mutagenesis experiments. The availability of this method, and the resulting models, has however been restricted by the availability of expensive computer hardware and software. To overcome these limitations, we have developed an environment for comparative protein modeling that consists of SWISS-MODEL, a server for automated comparative protein modeling and of the SWISS-PdbViewer, a sequence to structure workbench. The Swiss-PdbViewer not only acts as a client for SWISS-MODEL, but also provides a large selection of structure analysis and display tools. In addition, we provide the SWISS-MODEL Repository, a database containing more than 3500 automatically generated protein models. By making such tools freely available to the scientific community, we hope to increase the use of protein structures and models in the process of experiment design.
10,713 citations
"Identification of protegrin-1 as a ..." refers methods in this paper
...Further, the modeled structure of PG4 was validated in Swiss PDB Viewer (Figure 3(a)) using Ramachandran plot (Morris, MacArthur, Hutchinson, & Thornton, 1992), where 88.24% amino acid residues were found in the core region and 11.76% in the generous and allowed regions, as shown in Figure 3(b)....
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...PG4 was modelled in Swiss PDB Viewer, by point mutating residues in PG3 and in PG5....
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...%) of PG4 with the remaining protegrins, 3D templates were chosen for modeling PG4 in Swiss PDB Viewer (Guex & Peitsch, 1997)....
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