Gastric cancer (GC) is the most common type of cancer of the digestive system with high morbidity and mortality. Chemotherapy and targeted therapy are used to treat patients with advanced GC. However, side effects and drug resistance to the two modalities remain the main challenges. The Buzhong Yiqi decoction (BZYQD), a classical traditional Chinese medicine formula, has been reported for the treatment of various types of cancers. However, the underlying pharmacological mechanism has not been fully elucidated. Therefore, this study integrated network pharmacology, molecular docking, cancer public databases, and cell experiments to explore the potential bioactive compounds and BZYQD's mechanism of action against GC. A total of 245 targets of BZYQD, 5291 GC‐related targets, and 186 were identified as their common targets through the database. Network analysis confirmed AKT1, TP53, TNF, and EGFR to be the core targets, while the main compounds observed were quercetin, kaempferol, and β‐Sitosterol. The core signaling pathways included PI3K‐AKT, MAPK, TNF, and IL‐17. Molecular docking revealed good binding activity for the main compounds and core targets. Based on the database's validation of core targets, a large number of core genes were verified to be consistent with this study. Quercetin, kaempferol, and β‐Sitosterol were found to significantly reduce the growth of GC cells in the MTT experiment. The current study revealed that BZYQD may inhibit GC progression by interfering with core targets such as AKT1, TP53, TNF, EGFR, and MAPK3, and by regulating the activity of PI3K‐AKT, MAPK, TNF, and IL‐17 signaling pathways.
{"title":"Molecular Mechanisms of Buzhong Yiqi Decoction in the Treatment of Gastric Cancer: A Network Pharmacology, Molecular Docking, and In Vitro Experimental Analysis","authors":"Panke Zeng, Xinyu Wu, Chen Chen, Jianing Zhang, Haroon ur Rashid, Pengfei Zhang","doi":"10.1002/pep2.24371","DOIUrl":"https://doi.org/10.1002/pep2.24371","url":null,"abstract":"Gastric cancer (GC) is the most common type of cancer of the digestive system with high morbidity and mortality. Chemotherapy and targeted therapy are used to treat patients with advanced GC. However, side effects and drug resistance to the two modalities remain the main challenges. The Buzhong Yiqi decoction (BZYQD), a classical traditional Chinese medicine formula, has been reported for the treatment of various types of cancers. However, the underlying pharmacological mechanism has not been fully elucidated. Therefore, this study integrated network pharmacology, molecular docking, cancer public databases, and cell experiments to explore the potential bioactive compounds and BZYQD's mechanism of action against GC. A total of 245 targets of BZYQD, 5291 GC‐related targets, and 186 were identified as their common targets through the database. Network analysis confirmed AKT1, TP53, TNF, and EGFR to be the core targets, while the main compounds observed were quercetin, kaempferol, and β‐Sitosterol. The core signaling pathways included PI3K‐AKT, MAPK, TNF, and IL‐17. Molecular docking revealed good binding activity for the main compounds and core targets. Based on the database's validation of core targets, a large number of core genes were verified to be consistent with this study. Quercetin, kaempferol, and β‐Sitosterol were found to significantly reduce the growth of GC cells in the MTT experiment. The current study revealed that BZYQD may inhibit GC progression by interfering with core targets such as AKT1, TP53, TNF, EGFR, and MAPK3, and by regulating the activity of PI3K‐AKT, MAPK, TNF, and IL‐17 signaling pathways.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"14 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141548870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This review examines the potential applications of peptides in biotechnology, medicine, and pharmacy, while highlighting the important antibacterial and antiviral properties of peptides. Peptides and chemical peptide synthesis have become a field of study that is gaining great momentum today. Some of the main reasons for this are high specificity, biodegradability and versatility of peptides. Peptides also have some specific properties that make them attractive for pharmaceutical development. As a case study, it can be used to create peptides that can be used to replace or fix damaged proteins in the body by mimicking the action of naturally occurring proteins. Delivering drugs or other therapeutic agents to specific cells or tissues is another method that can help increase the effectiveness of treatment and reduce unwanted effects. Various types of antimicrobial peptides (AMPs), such as defensins and cathelicidins, and their anti‐infective properties are also discussed. Finally, peptides (melittin, lactoferricin, etc.) can be used to trigger an immune response against certain infections, such as COVID‐19 and Zika virus, by acting as vaccines. In our study, a comprehensive review was made on antiviral and AMPs, and especially peptides containing arginine and lysine were mentioned. The properties of these peptides, examples of these peptides and their developments in the pharmaceutical field are emphasized.
{"title":"Chemically Peptide Synthesis and Role of Arginine and Lysine in the Antimicrobial and Antiviral Activity of Synthetic Peptides: A Comprehensive Review","authors":"Selin Zeynep Sunar, Tayfun Acar, Fikrettin Sahin","doi":"10.1002/pep2.24368","DOIUrl":"https://doi.org/10.1002/pep2.24368","url":null,"abstract":"This review examines the potential applications of peptides in biotechnology, medicine, and pharmacy, while highlighting the important antibacterial and antiviral properties of peptides. Peptides and chemical peptide synthesis have become a field of study that is gaining great momentum today. Some of the main reasons for this are high specificity, biodegradability and versatility of peptides. Peptides also have some specific properties that make them attractive for pharmaceutical development. As a case study, it can be used to create peptides that can be used to replace or fix damaged proteins in the body by mimicking the action of naturally occurring proteins. Delivering drugs or other therapeutic agents to specific cells or tissues is another method that can help increase the effectiveness of treatment and reduce unwanted effects. Various types of antimicrobial peptides (AMPs), such as defensins and cathelicidins, and their anti‐infective properties are also discussed. Finally, peptides (melittin, lactoferricin, etc.) can be used to trigger an immune response against certain infections, such as COVID‐19 and Zika virus, by acting as vaccines. In our study, a comprehensive review was made on antiviral and AMPs, and especially peptides containing arginine and lysine were mentioned. The properties of these peptides, examples of these peptides and their developments in the pharmaceutical field are emphasized.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"50 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141530205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Latroeggtoxin‐VI (LETX‐VI), a peptide toxin discovered from the eggs of spider Latrodectus tredecimguttatus, was previously shown to promote the synthesis and release of dopamine in rat pheochromocytoma (PC12) cells, showing potential applications in the neurobiology and medicine. To further understand the structure and properties of LETX‐VI, the key residues were identified and their roles in the structure, function, and stability of LETX‐VI were analyzed in the present work. Based on the protein molecular docking, our previous work, and the relevant literature, the potential key residues of LETX‐VI were selected and identified by alanine‐scanning mutagenesis. The wild‐type LETX‐VI and its 13 mutants, including a double mutant, were prepared by gene cloning and heterologous expression in Escherichia coli, followed by activity, structure, and stability determination. The results demonstrated that the activity of the mutants K25A, R35A, K40A/R41A, and L45A, particularly R35A, to promote dopamine release from PC12 cells was significantly decreased compared with that of the wild‐type LETX‐VI, indicating that these mutated residues are the key residues. Circular dichroism (CD) analysis showed that the secondary structure of these mutants was not obviously different from that of wild‐type LETX‐VI, suggesting that mutation‐caused decrease in the activity of LETX‐VI is due to the changes in the binding site on the molecule surface, rather than the abnormal alternation of the molecular conformation of LETX‐VI. Acetonitrile (ACN) did not obviously influence the activity of LETX‐VI; however, 0.1% trifluoroacetic acid (TFA) treatment for 2 h significantly reduced its activity. Treatment with weakly acidic and basic buffers (pH ≥ 6.6) for 12 h was favorable for LETX‐VI and R35A to exert their activity. Higher temperatures (>37°C) decreased the activity of both wild‐type LETX‐VI and R35A. In conclusion, K25, R35, K40, R41, and L45 particularly R35 are the important functional site residues; during experiments, care should be taken to avoid the adverse influence of strong acid and high temperature on LETX‐VI. These observations have enhanced our understanding of the structure and properties of LETX‐VI and provided references for the subsequent modification of structure and function of LETX‐VI.
{"title":"Structure–Function Relationship and Stability of Latroeggtoxin‐VI: A Proteinaceous Toxin From the Eggs of Latrodectus tredecimguttatus","authors":"Si Chen, Minglu Sun, Panfeng Yin, Xianchun Wang","doi":"10.1002/pep2.24367","DOIUrl":"https://doi.org/10.1002/pep2.24367","url":null,"abstract":"Latroeggtoxin‐VI (LETX‐VI), a peptide toxin discovered from the eggs of spider <jats:italic>Latrodectus tredecimguttatus</jats:italic>, was previously shown to promote the synthesis and release of dopamine in rat pheochromocytoma (PC12) cells, showing potential applications in the neurobiology and medicine. To further understand the structure and properties of LETX‐VI, the key residues were identified and their roles in the structure, function, and stability of LETX‐VI were analyzed in the present work. Based on the protein molecular docking, our previous work, and the relevant literature, the potential key residues of LETX‐VI were selected and identified by alanine‐scanning mutagenesis. The wild‐type LETX‐VI and its 13 mutants, including a double mutant, were prepared by gene cloning and heterologous expression in <jats:italic>Escherichia coli</jats:italic>, followed by activity, structure, and stability determination. The results demonstrated that the activity of the mutants K25A, R35A, K40A/R41A, and L45A, particularly R35A, to promote dopamine release from PC12 cells was significantly decreased compared with that of the wild‐type LETX‐VI, indicating that these mutated residues are the key residues. Circular dichroism (CD) analysis showed that the secondary structure of these mutants was not obviously different from that of wild‐type LETX‐VI, suggesting that mutation‐caused decrease in the activity of LETX‐VI is due to the changes in the binding site on the molecule surface, rather than the abnormal alternation of the molecular conformation of LETX‐VI. Acetonitrile (ACN) did not obviously influence the activity of LETX‐VI; however, 0.1% trifluoroacetic acid (TFA) treatment for 2 h significantly reduced its activity. Treatment with weakly acidic and basic buffers (pH ≥ 6.6) for 12 h was favorable for LETX‐VI and R35A to exert their activity. Higher temperatures (>37°C) decreased the activity of both wild‐type LETX‐VI and R35A. In conclusion, K25, R35, K40, R41, and L45 particularly R35 are the important functional site residues; during experiments, care should be taken to avoid the adverse influence of strong acid and high temperature on LETX‐VI. These observations have enhanced our understanding of the structure and properties of LETX‐VI and provided references for the subsequent modification of structure and function of LETX‐VI.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"28 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141510809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Here, we describe a new technology, designed to accelerate peptide discovery by quick identification and optimization of the residues critical for protein–protein interactions or ligand binding. We called it PepFusion. It is based on ligation of short DNA sequences generated from known ligand‐binding regions. We tested it by selecting peptide antagonists of interleukin‐6 (IL‐6), a key mediator of inflammatory diseases such as rheumatoid arthritis (RA), Crohn's disease, and Castleman disease (CD). The PepFusion library demonstrated superiority over a random library by yielding a peptide with low micromolar affinity for IL‐6, whereas the random library failed. The affinity of the peptide from the PepFusion library was further enhanced by additional rounds of mutagenesis leading to peptide variants with low nanomolar IL‐6 affinity. In addition to generating high‐affinity peptides, our method opens the way to solve the problem of the false positive sequences, which are common with all display technologies.
在这里，我们介绍一种新技术，旨在通过快速识别和优化对蛋白质-蛋白质相互作用或配体结合至关重要的残基，加速多肽的发现。我们称之为 PepFusion。它基于从已知配体结合区域生成的短 DNA 序列的连接。我们通过选择白细胞介素-6（IL-6）的多肽拮抗剂对其进行了测试，IL-6是类风湿性关节炎（RA）、克罗恩病和卡斯特曼病（CD）等炎症性疾病的主要介质。与随机文库相比，PepFusion 文库的优势在于能产生对 IL-6 具有低微摩亲和力的多肽，而随机文库则失败了。PepFusion 文库中多肽的亲和力通过多轮诱变得到进一步提高，从而产生了具有低纳摩尔 IL-6 亲和力的多肽变体。除了生成高亲和力的多肽外，我们的方法还为解决假阳性序列问题开辟了道路，而假阳性序列是所有显示技术的通病。
{"title":"From Protein to a Bioactive Peptide: Potent IL‐6 Peptide Antagonist Generated by a Novel Method","authors":"Alexander Pisarchik, Noreen Gervasi, Edmund Nesti","doi":"10.1002/pep2.24370","DOIUrl":"https://doi.org/10.1002/pep2.24370","url":null,"abstract":"Here, we describe a new technology, designed to accelerate peptide discovery by quick identification and optimization of the residues critical for protein–protein interactions or ligand binding. We called it PepFusion. It is based on ligation of short DNA sequences generated from known ligand‐binding regions. We tested it by selecting peptide antagonists of interleukin‐6 (IL‐6), a key mediator of inflammatory diseases such as rheumatoid arthritis (RA), Crohn's disease, and Castleman disease (CD). The PepFusion library demonstrated superiority over a random library by yielding a peptide with low micromolar affinity for IL‐6, whereas the random library failed. The affinity of the peptide from the PepFusion library was further enhanced by additional rounds of mutagenesis leading to peptide variants with low nanomolar IL‐6 affinity. In addition to generating high‐affinity peptides, our method opens the way to solve the problem of the false positive sequences, which are common with all display technologies.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"50 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141510890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michele Larocca, Giuseppe Floresta, Daniele Verderese, Agostino Cilibrizzi
The folding of peptides and proteins is rigidly reliant on the ‘chemical information’ carried by the specific amino acid sequence. In this study, three polypeptides (PDBs: 2jof, 1res and 1prv) were investigated as model systems to assess their folded features, thereby enabling further understanding of mechanisms that play a role in regulating the folding process more widely. A novel physico‐chemical approach of analysis is proposed herein, focusing on chemical interactions and their related mechanical forces that we trust are determinant to drive the folding. Through this methodology, we have predicted the conformations adopted by the three polypeptides and compared the outcomes to those experimentally determined, achieving a substantial structural agreement. Molecular dynamic simulations have been carried out to further support our calculations and structural results. Within the three models, we demonstrate that the interaction of each amino acid residue with its neighbour residues is a crucial determinant for the formation of the 3D stable native structures. This article provides initial evidence that the folding occurs by means of mechanical forces developed upon establishing chemical interactions amongst residues, which, in turn, are peculiar to each specific amino acid present in each position of the peptide chain.
{"title":"‘Main Mechanical Forces‐Chemical Interactions’ Interplay as a Tool to Elucidate Folding Mechanisms","authors":"Michele Larocca, Giuseppe Floresta, Daniele Verderese, Agostino Cilibrizzi","doi":"10.1002/pep2.24365","DOIUrl":"https://doi.org/10.1002/pep2.24365","url":null,"abstract":"The folding of peptides and proteins is rigidly reliant on the ‘chemical information’ carried by the specific amino acid sequence. In this study, three polypeptides (PDBs: 2jof, 1res and 1prv) were investigated as model systems to assess their folded features, thereby enabling further understanding of mechanisms that play a role in regulating the folding process more widely. A novel physico‐chemical approach of analysis is proposed herein, focusing on chemical interactions and their related mechanical forces that we trust are determinant to drive the folding. Through this methodology, we have predicted the conformations adopted by the three polypeptides and compared the outcomes to those experimentally determined, achieving a substantial structural agreement. Molecular dynamic simulations have been carried out to further support our calculations and structural results. Within the three models, we demonstrate that the interaction of each amino acid residue with its neighbour residues is a crucial determinant for the formation of the 3D stable native structures. This article provides initial evidence that the folding occurs by means of mechanical forces developed upon establishing chemical interactions amongst residues, which, in turn, are peculiar to each specific amino acid present in each position of the peptide chain.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"42 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141196726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gabriela R. Barredo‐Vacchelli, Jésica A. Rodríguez, Joaquin A. Eloy, Silvia A. Camperi
Liraglutide, developed by Novo Nordisk, is applied in Type 2 diabetes and obesity treatment. Several solid‐phase peptide synthesis protocols were designed for its production. However, current protocols are expensive and many of them are difficult to scale‐up. In this study, a novel alternative for liraglutide production was developed. The peptide was elongated by Fmoc/tBu solid‐phase peptide synthesis on 4‐hydroxymethylbenzoyl–ChemMatrix (HMBA‐CM) resin using the chaotropic agent LiCl as an additive to prevent peptide aggregation. After elongation, removal of side‐chain protecting groups and peptide cleavage from the resin was performed by a two‐stage procedure. Side‐chain protecting groups were removed with 92.5% TFA, leaving the unprotected peptide attached to the solid support. The resin was thoroughly washed to eliminate the contaminants. Next, peptide release was achieved by treating the peptidyl resin with NaOH 0.1 N. This two‐stage procedure assures a high‐purity product without the need of using a large amount of ether as in previous protocols. Finally, liraglutide was purified by hydrophobic interaction with low‐pressure liquid chromatography (HI‐LPLC) instead of using the expensive RP‐HPLC applied in reported methods. This simple and economic method resulted in a high yield and a purity product while overcoming the high cost and difficulties of current processes.
{"title":"A Novel Method for Liraglutide Synthesis and Purification","authors":"Gabriela R. Barredo‐Vacchelli, Jésica A. Rodríguez, Joaquin A. Eloy, Silvia A. Camperi","doi":"10.1002/pep2.24351","DOIUrl":"https://doi.org/10.1002/pep2.24351","url":null,"abstract":"Liraglutide, developed by Novo Nordisk, is applied in Type 2 diabetes and obesity treatment. Several solid‐phase peptide synthesis protocols were designed for its production. However, current protocols are expensive and many of them are difficult to scale‐up. In this study, a novel alternative for liraglutide production was developed. The peptide was elongated by Fmoc/tBu solid‐phase peptide synthesis on 4‐hydroxymethylbenzoyl–ChemMatrix (HMBA‐CM) resin using the chaotropic agent LiCl as an additive to prevent peptide aggregation. After elongation, removal of side‐chain protecting groups and peptide cleavage from the resin was performed by a two‐stage procedure. Side‐chain protecting groups were removed with 92.5% TFA, leaving the unprotected peptide attached to the solid support. The resin was thoroughly washed to eliminate the contaminants. Next, peptide release was achieved by treating the peptidyl resin with NaOH 0.1 N. This two‐stage procedure assures a high‐purity product without the need of using a large amount of ether as in previous protocols. Finally, liraglutide was purified by hydrophobic interaction with low‐pressure liquid chromatography (HI‐LPLC) instead of using the expensive RP‐HPLC applied in reported methods. This simple and economic method resulted in a high yield and a purity product while overcoming the high cost and difficulties of current processes.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"116 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140836504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kunal Bhattacharya, Atanu Bhattacharjee, Manodeep Chakraborty, Dibyajyoti Das
Alzheimer's disease (AD) is a serious neurodegenerative disorder that results in cognitive deterioration, amnesia, and alterations in behavior, rendering it a significant issue in public health. The pathogenesis involves amyloid plaques highlighting the importance of targeting BACE1. This study explores fluspirilene, a di‐phenyl‐butyl‐piperidine as a potential BACE1 inhibitor for AD treatment. Fluspirilene was analyzed for ADMET. In silico molecular docking assessed fluspirilene's binding affinity with BACE1. Re‐docking a co‐crystallized ligand confirmed the docking process. Molecular dynamics simulations and related multifaceted computational analyses were conducted to assess the stability of docked complexes. Fluspirilene had good physicochemical and pharmacokinetic characteristics according to ADMET profiling. In silico molecular docking showed multiple BACE1 interactions with a binding affinity of −9.2 kcal/mol and fluspirilene–BACE1 complex stability was confirmed by molecular dynamics simulation results. Possible therapeutic applications in lowering Aβ generation and treating AD are indicated by the compound's pharmacokinetics, molecular interactions, and binding energetics. Validation and optimization of experiments are necessary for the clinical development of fluspirilene as a BACE1 inhibitor for AD.
{"title":"Molecular Dynamics and Binding Energetics of Fluspirilene With BACE1: Implications for Alzheimer's Disease Intervention","authors":"Kunal Bhattacharya, Atanu Bhattacharjee, Manodeep Chakraborty, Dibyajyoti Das","doi":"10.1002/pep2.24349","DOIUrl":"https://doi.org/10.1002/pep2.24349","url":null,"abstract":"Alzheimer's disease (AD) is a serious neurodegenerative disorder that results in cognitive deterioration, amnesia, and alterations in behavior, rendering it a significant issue in public health. The pathogenesis involves amyloid plaques highlighting the importance of targeting BACE1. This study explores fluspirilene, a di‐phenyl‐butyl‐piperidine as a potential BACE1 inhibitor for AD treatment. Fluspirilene was analyzed for ADMET. In silico molecular docking assessed fluspirilene's binding affinity with BACE1. Re‐docking a co‐crystallized ligand confirmed the docking process. Molecular dynamics simulations and related multifaceted computational analyses were conducted to assess the stability of docked complexes. Fluspirilene had good physicochemical and pharmacokinetic characteristics according to ADMET profiling. In silico molecular docking showed multiple BACE1 interactions with a binding affinity of −9.2 kcal/mol and fluspirilene–BACE1 complex stability was confirmed by molecular dynamics simulation results. Possible therapeutic applications in lowering Aβ generation and treating AD are indicated by the compound's pharmacokinetics, molecular interactions, and binding energetics. Validation and optimization of experiments are necessary for the clinical development of fluspirilene as a BACE1 inhibitor for AD.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"35 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140572981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Porphyromonas gingivalis and Fusobacterium nucleatum are known to contribute to a variety of tumorigenic pathways linked to the progression of oral squamous cell carcinoma (OSCC). The growing global incidence of antibiotic resistance highlights the critical need to consider the use of antimicrobial peptides (AMPs) as a viable alternative to conventional antibiotics. The current study comprehensively tested Lactobacillus sp.−derived AMPs against bacterially exacerbated OSCC. A total of 52 AMPs were obtained from various databases, and an in silico analysis determined their potent antibacterial and anticancer characteristics after a rigorous screening and pruning approach. Twelve AMPs were tested for 3D structural alignment prediction and validation, with the GH12 synthetic AMP serving as a control. These candidate peptides were thoroughly screened against six important virulence proteins of P. gingivalis and four of F. nucleatum, with the lowest energy score of the docked complexes measuring binding affinity and interactions with active residues being chosen. plpl_18 was determined as the most efficient new AMP that interacted with the virulence protein RagB of P. gingivalis and Fap2 of F. nucleatum with docking scores of −238.24 and −254.27 kcal/mol, respectively. This AMP plpl_18 was docked against selective target OSCC regulatory proteins such as cytokines, metallomatrix proteinase, MAPK, E‐cadherin, and JAK‐1 proteins. Among these proteins, it docked against matrix metalloproteinase‐9 with the highest negative docking scores of −7.5, −260.956, and −1361.9 kcal/mol using AutoDock Vina, HPEPDOCK, and ClusPro 2.0, respectively. Molecular dynamic simulation was used to perform extrapolated validation. These computational studies provide an essential foundation for anticipated laboratory and clinical investigations concerning the possibility of adapting therapeutic peptides based on probiotics to combat the proliferation of OSCC, which is accelerated by F. nucleatum and P. gingivalis.
{"title":"In Silico Prediction and Molecular Simulation of Antimicrobial Peptide Variants From Lactobacillus sp. Against Porphyromonas gingivalis and Fusobacterium nucleatum in Oral Squamous Cell Carcinoma","authors":"Zarin Taj, Indranil Chattopadhyay","doi":"10.1002/pep2.24348","DOIUrl":"https://doi.org/10.1002/pep2.24348","url":null,"abstract":"<jats:italic>Porphyromonas gingivalis</jats:italic> and <jats:italic>Fusobacterium nucleatum</jats:italic> are known to contribute to a variety of tumorigenic pathways linked to the progression of oral squamous cell carcinoma (OSCC). The growing global incidence of antibiotic resistance highlights the critical need to consider the use of antimicrobial peptides (AMPs) as a viable alternative to conventional antibiotics. The current study comprehensively tested <jats:italic>Lactobacillus</jats:italic> sp.−derived AMPs against bacterially exacerbated OSCC. A total of 52 AMPs were obtained from various databases, and an in silico analysis determined their potent antibacterial and anticancer characteristics after a rigorous screening and pruning approach. Twelve AMPs were tested for 3D structural alignment prediction and validation, with the GH12 synthetic AMP serving as a control. These candidate peptides were thoroughly screened against six important virulence proteins of <jats:italic>P. gingivalis</jats:italic> and four of <jats:italic>F. nucleatum</jats:italic>, with the lowest energy score of the docked complexes measuring binding affinity and interactions with active residues being chosen. plpl_18 was determined as the most efficient new AMP that interacted with the virulence protein RagB of <jats:italic>P. gingivalis</jats:italic> and Fap2 of <jats:italic>F. nucleatum</jats:italic> with docking scores of −238.24 and −254.27 kcal/mol, respectively. This AMP plpl_18 was docked against selective target OSCC regulatory proteins such as cytokines, metallomatrix proteinase, MAPK, E‐cadherin, and JAK‐1 proteins. Among these proteins, it docked against matrix metalloproteinase‐9 with the highest negative docking scores of −7.5, −260.956, and −1361.9 kcal/mol using AutoDock Vina, HPEPDOCK, and ClusPro 2.0, respectively. Molecular dynamic simulation was used to perform extrapolated validation. These computational studies provide an essential foundation for anticipated laboratory and clinical investigations concerning the possibility of adapting therapeutic peptides based on probiotics to combat the proliferation of OSCC, which is accelerated by <jats:italic>F. nucleatum</jats:italic> and <jats:italic>P. gingivalis</jats:italic>.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"59 Pt A 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140074690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matheus Nolasco, Douglas O. C. Mariano, Daniel C. Pimenta, Humberto Fonseca de Freitas, Samuel Silva da Rocha Pita, Alexsandro Branco
Wasps have been neglected in toxinological studies, even with their diversity of species, when compared to other groups of venomous animals such as snakes, scorpions, and spiders. Solitary wasps, such as Pepsis decorata, are known for their mechanism of total or temporary paralysis of the host. In addition, their venoms are considered sources for studies of small peptides, bioactive peptides with neural and antimicrobial activities. In this work, some oligopeptides were analyzed by de novo sequencing identifying 39 oligopeptide sequences. Some sequences were similar to proctolin, a bradykinin-potentiating peptide, and poneritoxin, one bradykinin-related peptide. As proctolin-like peptides were the major constituent in distinct experimental conditions, it was selected for further in silico studies in order to understand its possible importance as a constituent of wasp venom and whether these peptides could be of biotechnological importance. We investigate its binding mode comparing with proctolin and we further analyzed the importance of the tyrosine-leucine-glutamic acid (YLE) tripeptide-motif conservation. This experimental, an in silico approach, increased the range of compounds identified in peptide analyses proving good characterization of little-known peptidic compounds.
{"title":"Oligopeptides analysis in spiderhawk's venom (Pepsis decorata Perty, 1833, Hymenoptera: Pompilidae)","authors":"Matheus Nolasco, Douglas O. C. Mariano, Daniel C. Pimenta, Humberto Fonseca de Freitas, Samuel Silva da Rocha Pita, Alexsandro Branco","doi":"10.1002/pep2.24347","DOIUrl":"https://doi.org/10.1002/pep2.24347","url":null,"abstract":"Wasps have been neglected in toxinological studies, even with their diversity of species, when compared to other groups of venomous animals such as snakes, scorpions, and spiders. Solitary wasps, such as <i>Pepsis decorata</i>, are known for their mechanism of total or temporary paralysis of the host. In addition, their venoms are considered sources for studies of small peptides, bioactive peptides with neural and antimicrobial activities. In this work, some oligopeptides were analyzed by de novo sequencing identifying 39 oligopeptide sequences. Some sequences were similar to proctolin, a bradykinin-potentiating peptide, and poneritoxin, one bradykinin-related peptide. As proctolin-like peptides were the major constituent in distinct experimental conditions, it was selected for further in silico studies in order to understand its possible importance as a constituent of wasp venom and whether these peptides could be of biotechnological importance. We investigate its binding mode comparing with proctolin and we further analyzed the importance of the tyrosine-leucine-glutamic acid (YLE) tripeptide-motif conservation. This experimental, an in silico approach, increased the range of compounds identified in peptide analyses proving good characterization of little-known peptidic compounds.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"12 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139769841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In the realm of therapeutic peptides, tremendous progress has been achieved in the last two decades. The building block of peptides that is, ‘Amino Acid’ has been modified by various chemical modifications such as side-chain alteration in linear peptides, cyclization, back-bone modification, pro-drug moiety, conjugation with heterocycles, and natural products to make peptides a foremost candidate as a therapeutic drug. Since the advent of insulin in 1922, peptides have immensely affected the development of the pharmaceutical industry giving rise to the peptide-based drug industry. In recent years, peptides having antimicrobial, antiviral, anti-tumor, anti-inflammatory, anti-aging, and antioxidant properties have developed. Also, it has now entered as a potent candidate in the field of oncology and also become a valuable tool as a radiolabeled peptide for the detection of various diseases. Generally, peptides were extracted from natural sources in the olden days, but presently work is directed towards finding alternate and sustainable ways for developing synthetic peptides. The present review covers the discussion about the historic evaluation of peptides, available effective synthetic processes, current advancements, use of bioinformatic tools, computational strategies, and the methodology to overcome the barrier for making peptides the potent candidate for the future world.
{"title":"Review on therapeutic potential of peptides: Advancements in synthesis methods, linear and cyclic peptides, and strategies for overcoming challenges","authors":"Naurin Lalani, Sunil Tivari, Vicky Jain, Yashwantsinh Jadeja","doi":"10.1002/pep2.24343","DOIUrl":"https://doi.org/10.1002/pep2.24343","url":null,"abstract":"In the realm of therapeutic peptides, tremendous progress has been achieved in the last two decades. The building block of peptides that is, ‘Amino Acid’ has been modified by various chemical modifications such as side-chain alteration in linear peptides, cyclization, back-bone modification, pro-drug moiety, conjugation with heterocycles, and natural products to make peptides a foremost candidate as a therapeutic drug. Since the advent of insulin in 1922, peptides have immensely affected the development of the pharmaceutical industry giving rise to the peptide-based drug industry. In recent years, peptides having antimicrobial, antiviral, anti-tumor, anti-inflammatory, anti-aging, and antioxidant properties have developed. Also, it has now entered as a potent candidate in the field of oncology and also become a valuable tool as a radiolabeled peptide for the detection of various diseases. Generally, peptides were extracted from natural sources in the olden days, but presently work is directed towards finding alternate and sustainable ways for developing synthetic peptides. The present review covers the discussion about the historic evaluation of peptides, available effective synthetic processes, current advancements, use of bioinformatic tools, computational strategies, and the methodology to overcome the barrier for making peptides the potent candidate for the future world.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"13 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139666748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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