Gupta Dheeraj Rajesh, Prarambh S. R. Dwivedi, Abel John Koshy, Anusha S, Ranjitha A, Niyas Rehman, Pankaj Kumar
Breast cancer, a formidable threat to women's health, mainly manifests in the HER2 subtype, affecting approximately one in five women. Thus, this study endeavors to pioneer novel approaches by exploring the efficacy of benzothiazole‐coupled azetidinone derivatives against EGFR. We aimed to elucidate their potential by employing a comprehensive array of in silico methodologies, including molecular docking, pharmacokinetics profiling, pharmacophore mapping, molecular dynamic simulations, and MMPBSA analysis. Remarkably, our results demonstrate that our designed molecules adhere to Lipinski's rule and comply with essential physiochemical and druggable properties, affirming the promise of these compounds. Ligand MS60 emerges as a lead, showcasing the most substantial interaction with the EGFR receptor, underscored by its impressive docking score of −8.199 kcal/mol. Furthermore, molecular dynamics simulations conducted via GROMACS corroborate the stability of the MS60‐EGFR complex, portraying minimal fluctuations. This assertion is further validated through MMPBSA, PCA analysis, DCCM, and FEL studies, underscoring the robustness of our findings. We have designed the pharmacophore model to unravel critical steric and electronic attributes essential for effective supramolecular interactions with the EGFR receptor. Notably, the presence of the R10, R11, and A4 groups within the ligands underscores their pivotal role in eliciting pharmacological activity, offering valuable insights for further exploration and development.
{"title":"Insights Into Benzothiazolyl‐Coupled Azetidinone Moieties Toward EGFR Binding and Stability Analysis—Evidence From Molecular Docking and Dynamics Simulation","authors":"Gupta Dheeraj Rajesh, Prarambh S. R. Dwivedi, Abel John Koshy, Anusha S, Ranjitha A, Niyas Rehman, Pankaj Kumar","doi":"10.1002/pep2.24382","DOIUrl":"https://doi.org/10.1002/pep2.24382","url":null,"abstract":"Breast cancer, a formidable threat to women's health, mainly manifests in the HER2 subtype, affecting approximately one in five women. Thus, this study endeavors to pioneer novel approaches by exploring the efficacy of benzothiazole‐coupled azetidinone derivatives against EGFR. We aimed to elucidate their potential by employing a comprehensive array of in silico methodologies, including molecular docking, pharmacokinetics profiling, pharmacophore mapping, molecular dynamic simulations, and MMPBSA analysis. Remarkably, our results demonstrate that our designed molecules adhere to Lipinski's rule and comply with essential physiochemical and druggable properties, affirming the promise of these compounds. Ligand MS60 emerges as a lead, showcasing the most substantial interaction with the EGFR receptor, underscored by its impressive docking score of −8.199 kcal/mol. Furthermore, molecular dynamics simulations conducted via GROMACS corroborate the stability of the MS60‐EGFR complex, portraying minimal fluctuations. This assertion is further validated through MMPBSA, PCA analysis, DCCM, and FEL studies, underscoring the robustness of our findings. We have designed the pharmacophore model to unravel critical steric and electronic attributes essential for effective supramolecular interactions with the EGFR receptor. Notably, the presence of the R10, R11, and A4 groups within the ligands underscores their pivotal role in eliciting pharmacological activity, offering valuable insights for further exploration and development.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"32 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182139","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}
Zahra Toutou, Sofiane Fatmi, Nacera Chibani, Katarzyna Pokajewicz, Mohamed Skiba, Piotr P. Wieczorek, Mokrane Iguerouada
Propolis, a bee product, is renowned globally for its diverse pharmacological activities attributed to its phenolic compounds, flavonoids, and terpenes. This study aims to identify the chemical compounds in Algerian raw propolis and evaluate the protective potential of its inclusion complex. Gas chromatography–mass spectrometry (GC/MS), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) were used for chemical characterization. Additionally, molecular docking against SARS‐COVID‐2 main proteases and ADMET profiling were conducted. The analysis revealed α‐pinene (25.29%–11.04%) and limonene (22.46%–12.88%) as the major components in raw propolis and its complex. DSC/TGA analysis demonstrated the protective effect of encapsulated molecules, with limonene and α‐pinene showing high activity against SARS‐COVID‐2 main proteases 7N5Z, 6LU7, and 7E6L, with docking scores of −5.71, −5.61, and −5.10 kcal/mol, respectively. This study highlights the potential of propolis constituents as drug candidates against the SARS‐COVID‐2 pandemic.
{"title":"Exploring the Therapeutic Potential of Algerian Propolis: GC/MS Profiling, Protective Inclusion Complex, and In Silico Evaluation Against SARS‐CoV‐2 Main Proteases","authors":"Zahra Toutou, Sofiane Fatmi, Nacera Chibani, Katarzyna Pokajewicz, Mohamed Skiba, Piotr P. Wieczorek, Mokrane Iguerouada","doi":"10.1002/pep2.24381","DOIUrl":"https://doi.org/10.1002/pep2.24381","url":null,"abstract":"Propolis, a bee product, is renowned globally for its diverse pharmacological activities attributed to its phenolic compounds, flavonoids, and terpenes. This study aims to identify the chemical compounds in Algerian raw propolis and evaluate the protective potential of its inclusion complex. Gas chromatography–mass spectrometry (GC/MS), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) were used for chemical characterization. Additionally, molecular docking against SARS‐COVID‐2 main proteases and ADMET profiling were conducted. The analysis revealed α‐pinene (25.29%–11.04%) and limonene (22.46%–12.88%) as the major components in raw propolis and its complex. DSC/TGA analysis demonstrated the protective effect of encapsulated molecules, with limonene and α‐pinene showing high activity against SARS‐COVID‐2 main proteases 7N5Z, 6LU7, and 7E6L, with docking scores of −5.71, −5.61, and −5.10 kcal/mol, respectively. This study highlights the potential of propolis constituents as drug candidates against the SARS‐COVID‐2 pandemic.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"23 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182136","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}
Catherine Bergeron, Christopher Bérubé, Henry Lamb, Yasuko Koda, David J. Craik, Sónia Troeira Henriques, Normand Voyer, Nicole Lawrence
Targeted melanoma therapies, including treatment with the small molecule drug dabrafenib, can become ineffective due to acquired drug resistance. Dabrafenib targets BRAF‐V600E, a mutation that is present in more than half of melanoma cancers. Therefore, drug discovery efforts need to explore alternative candidate molecules that selectively target and kill melanoma cells via mechanisms different to those of current drugs. Marine fungi are an underexplored resource for bioactive molecules. Mortiamide‐D, a seven amino acid cyclic peptide from Mortierella sp, is an example molecule with desirable features for drug development. We synthesized mortiamide‐D and three rationally designed analogs and observed modest micromolar activity against HT144 melanoma cells that are sensitive or resistant to dabrafenib. By contrast, mortiamide‐D and analogs did not kill noncancer HaCaT cells at these concentrations. Substitution of D‐Ile at position 7 with D‐Arg improved membrane permeability and enhanced potency against HT144 cells via a mode‐of‐action that includes perturbation of mitochondrial membrane potential. These studies suggest the potential of mortiamides as modifiable scaffolds for developing a new class of molecule for targeting melanoma cells.
{"title":"Analogs of Cyclic Peptide Mortiamide‐D From Marine Fungi Have Improved Membrane Permeability and Kill Drug‐Resistant Melanoma Cells","authors":"Catherine Bergeron, Christopher Bérubé, Henry Lamb, Yasuko Koda, David J. Craik, Sónia Troeira Henriques, Normand Voyer, Nicole Lawrence","doi":"10.1002/pep2.24380","DOIUrl":"https://doi.org/10.1002/pep2.24380","url":null,"abstract":"Targeted melanoma therapies, including treatment with the small molecule drug dabrafenib, can become ineffective due to acquired drug resistance. Dabrafenib targets BRAF‐V600E, a mutation that is present in more than half of melanoma cancers. Therefore, drug discovery efforts need to explore alternative candidate molecules that selectively target and kill melanoma cells via mechanisms different to those of current drugs. Marine fungi are an underexplored resource for bioactive molecules. Mortiamide‐D, a seven amino acid cyclic peptide from <jats:italic>Mortierella</jats:italic> sp, is an example molecule with desirable features for drug development. We synthesized mortiamide‐D and three rationally designed analogs and observed modest micromolar activity against HT144 melanoma cells that are sensitive or resistant to dabrafenib. By contrast, mortiamide‐D and analogs did not kill noncancer HaCaT cells at these concentrations. Substitution of D‐Ile at position 7 with D‐Arg improved membrane permeability and enhanced potency against HT144 cells via a mode‐of‐action that includes perturbation of mitochondrial membrane potential. These studies suggest the potential of mortiamides as modifiable scaffolds for developing a new class of molecule for targeting melanoma cells.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"50 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182137","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}
Glucose abnormality is one of the atypical symptoms mostly overlooked during severe malaria. Screening for proteases involved in glucose abnormality suggests a potential new drug target. PF11_0189 is a putative insulin degrading enzyme found in the genome of Plasmodium falciparum. In silico approach revealed that PF11_0189 is similar to the metalloproteases exhibiting a zinc binding motif. The substrate binding region of PF11_0189 catalytic domain is lined by residues of a mixed nature, enabling the accommodation of both hydrophobic and hydrophilic residues from substrates. Analysis of each amino acid position from combinatorial peptide library suggests Thr and Ser to be the most crucial residues as upon its mutation significant improvement is observed in the binding. The peptides P‐21 (VPICSLY), P‐70 (TMICVLY), and P‐121 (AVICSLY) demonstrate significantly better interaction within the active site than a template peptide (TSICSLY). Molecular dynamic simulations confirm the complex's integrity, with all structures within the qualitative limit of compactness and stability during the simulation time. Principal component analysis (PCA) reveals major conformational motions and different energy landscapes, while dynamic cross‐correlation matrix (DCCM) highlights residue interactions of the complexes. The insights obtained through computational methods provide clues about substrate selectivity in PF11_0189, which can be utilized for peptide‐based therapeutics against severe malaria.
{"title":"In Silico Analysis of Conformational Dynamics and Energetic Landscapes of Putative Insulinase PF11_0189 From the Plasmodium falciparum Genome With Insulin‐Derived Peptides: Approach to Rationale Design of Insulin Peptide‐Based Inhibitors","authors":"Prabhash Jyoti Mahanta, Kimjolly Lhouvum","doi":"10.1002/pep2.24377","DOIUrl":"https://doi.org/10.1002/pep2.24377","url":null,"abstract":"Glucose abnormality is one of the atypical symptoms mostly overlooked during severe malaria. Screening for proteases involved in glucose abnormality suggests a potential new drug target. PF11_0189 is a putative insulin degrading enzyme found in the genome of <jats:italic>Plasmodium falciparum.</jats:italic> In silico approach revealed that PF11_0189 is similar to the metalloproteases exhibiting a zinc binding motif. The substrate binding region of PF11_0189 catalytic domain is lined by residues of a mixed nature, enabling the accommodation of both hydrophobic and hydrophilic residues from substrates. Analysis of each amino acid position from combinatorial peptide library suggests Thr and Ser to be the most crucial residues as upon its mutation significant improvement is observed in the binding. The peptides P‐21 (VPICSLY), P‐70 (TMICVLY), and P‐121 (AVICSLY) demonstrate significantly better interaction within the active site than a template peptide (TSICSLY). Molecular dynamic simulations confirm the complex's integrity, with all structures within the qualitative limit of compactness and stability during the simulation time. Principal component analysis (PCA) reveals major conformational motions and different energy landscapes, while dynamic cross‐correlation matrix (DCCM) highlights residue interactions of the complexes. The insights obtained through computational methods provide clues about substrate selectivity in PF11_0189, which can be utilized for peptide‐based therapeutics against severe malaria.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"32 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182138","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}
Antimicrobial peptides (AMPs) are being studied for their potential in addressing microbial resistance, a significant issue in treating infections. More than 22,500 AMPs are listed in the database, but their clinical use faces challenges like instability and selectivity. Nanodrug delivery systems are now seen as a beneficial method to improve the effectiveness of AMPs. These systems can shield AMPs from degradation, enhance their availability, and deliver them to specific infection sites, enhancing their ability to combat resistance. One example is liposomal nanoparticles loaded with a mix of AMPs, targeting drug‐resistant bacteria directly. Strategies to develop novel AMPs through engineering methods, including design approaches, computational techniques, and modifications for stability, are discussed in this review. Combinatorial approaches with antibiotics, patents, and clinical trials involving AMPs against infections are also considered, highlighting the potential of AMPs in battling microbial resistance.
{"title":"Empowering Antimicrobial Peptides: Harnessing Nanotechnology and Engineering Strategies to Combat Microbial Resistance","authors":"Dubey Avinash, Anjali Bisht, Manish Kumar, Shubham Thakur, Preeti Patel, Balak Das Kurmi","doi":"10.1002/pep2.24376","DOIUrl":"https://doi.org/10.1002/pep2.24376","url":null,"abstract":"Antimicrobial peptides (AMPs) are being studied for their potential in addressing microbial resistance, a significant issue in treating infections. More than 22,500 AMPs are listed in the database, but their clinical use faces challenges like instability and selectivity. Nanodrug delivery systems are now seen as a beneficial method to improve the effectiveness of AMPs. These systems can shield AMPs from degradation, enhance their availability, and deliver them to specific infection sites, enhancing their ability to combat resistance. One example is liposomal nanoparticles loaded with a mix of AMPs, targeting drug‐resistant bacteria directly. Strategies to develop novel AMPs through engineering methods, including design approaches, computational techniques, and modifications for stability, are discussed in this review. Combinatorial approaches with antibiotics, patents, and clinical trials involving AMPs against infections are also considered, highlighting the potential of AMPs in battling microbial resistance.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"15 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141885875","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}
Nurkhodja Mukhamedov, Akmal M. Asrorov, Muzaffar Kayumov, Ahmidin Wali, Haji Akber Aisa, Sharafitdin Mirzaakhmedov, Abulimiti Yili
Zinc is the second most valuable microelement after iron, according to its abundance in the human body. Supplementation of this metal is not straightforward because of several factors like phytates and interference of other minerals during gastrointestinal digestion. For the last several years, intensive research has been developing new forms of zinc supplements based on zinc‐binding peptides from food products. Except for the advantages of supplementation, zinc‐peptide complexes are expected to be drug candidates against various diseases. Zinc supplementation can be improved by protein hydrolysates and peptides due to their zinc‐binding ability. They enhance zinc supplementation and contribute to preventing conditions leading to zinc deficiency that cause various diseases. Research on food‐derived zinc‐binding peptides is progressing in two directions: the isolation and identification of individual peptides (1) and the preparation of zinc complexes of protein hydrolysates (2). Both approaches are primarily aimed at developing effective mineral supplements, although some work on the second approach is also related to nutrition and therapy. Because zinc–protein hydrolysate complexes are nonstandardized mixtures of peptides, their biological activity mechanisms can be difficult to study. Therefore, it is important to focus more research on the biological activity of individual zinc‐binding complexes and their zinc complexes. This work reviewed recent advances in isolating and identifying zinc‐binding peptides from food sources, preparing protein hydrolysate–zinc complexes, and their biological activities. The established sequences of zinc‐binding peptides have been compiled into a table to review their amino‐acid composition and sequence. We also highlighted approaches for isolating and determining the zinc‐binding capacity of peptides in this class. The structural features of peptides affecting their zinc‐binding property were discussed in one section.
{"title":"Food Protein‐Derived Zinc‐Binding Peptides: Isolation, Purification, and Biological Aspects","authors":"Nurkhodja Mukhamedov, Akmal M. Asrorov, Muzaffar Kayumov, Ahmidin Wali, Haji Akber Aisa, Sharafitdin Mirzaakhmedov, Abulimiti Yili","doi":"10.1002/pep2.24369","DOIUrl":"https://doi.org/10.1002/pep2.24369","url":null,"abstract":"Zinc is the second most valuable microelement after iron, according to its abundance in the human body. Supplementation of this metal is not straightforward because of several factors like phytates and interference of other minerals during gastrointestinal digestion. For the last several years, intensive research has been developing new forms of zinc supplements based on zinc‐binding peptides from food products. Except for the advantages of supplementation, zinc‐peptide complexes are expected to be drug candidates against various diseases. Zinc supplementation can be improved by protein hydrolysates and peptides due to their zinc‐binding ability. They enhance zinc supplementation and contribute to preventing conditions leading to zinc deficiency that cause various diseases. Research on food‐derived zinc‐binding peptides is progressing in two directions: the isolation and identification of individual peptides (1) and the preparation of zinc complexes of protein hydrolysates (2). Both approaches are primarily aimed at developing effective mineral supplements, although some work on the second approach is also related to nutrition and therapy. Because zinc–protein hydrolysate complexes are nonstandardized mixtures of peptides, their biological activity mechanisms can be difficult to study. Therefore, it is important to focus more research on the biological activity of individual zinc‐binding complexes and their zinc complexes. This work reviewed recent advances in isolating and identifying zinc‐binding peptides from food sources, preparing protein hydrolysate–zinc complexes, and their biological activities. The established sequences of zinc‐binding peptides have been compiled into a table to review their amino‐acid composition and sequence. We also highlighted approaches for isolating and determining the zinc‐binding capacity of peptides in this class. The structural features of peptides affecting their zinc‐binding property were discussed in one section.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"67 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777242","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}
Krista K. Alexander, Michalis Kentros, Leah G. Helton, Dimitris Tantis‐Tapeinos, Timothy J. LeClair, Fredejah T. Royer, Neil J. Grimsey, Alexia V. Polissidis, Eileen J. Kennedy, Hardy J. Rideout
Mutations in the gene encoding leucine‐rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). The reduced penetrance of mutations in the LRRK2 gene has also led to variants appearing in seemingly sporadic forms of the disease. Kinase inhibition effectively blocks neuronal death and small‐molecule Class I inhibitors are proceeding through clinical trials in multiple PD cohorts. The toxic interaction between mutant LRRK2 and FADD lies downstream of its kinase activity and is required to induce neuronal death. The present study aimed to determine whether the FADD‐LRRK2 interface could be disrupted and what effects this may have on neuroprotection. A series of constrained peptides were designed to mimic the alpha‐helical protein interaction interface between the LRRK2 armadillo region and the death domain of FADD. These peptide‐based protein–protein interaction inhibitors significantly reduced this interaction and blocked apoptotic death of primary neurons expressing G2019S‐LRRK2. This work has identified novel constrained peptides that disrupt the LRRK2‐FADD interface and downregulate mutant LRRK2‐induced neuronal death in an allosteric manner, thereby providing a potential alternative therapeutic approach for PD.
{"title":"Disruption of the LRRK2‐FADD Interface Using Constrained Peptides","authors":"Krista K. Alexander, Michalis Kentros, Leah G. Helton, Dimitris Tantis‐Tapeinos, Timothy J. LeClair, Fredejah T. Royer, Neil J. Grimsey, Alexia V. Polissidis, Eileen J. Kennedy, Hardy J. Rideout","doi":"10.1002/pep2.24374","DOIUrl":"https://doi.org/10.1002/pep2.24374","url":null,"abstract":"Mutations in the gene encoding leucine‐rich repeat kinase 2 (<jats:italic>LRRK2</jats:italic>) are the most common cause of familial Parkinson's disease (PD). The reduced penetrance of mutations in the LRRK2 gene has also led to variants appearing in seemingly sporadic forms of the disease. Kinase inhibition effectively blocks neuronal death and small‐molecule Class I inhibitors are proceeding through clinical trials in multiple PD cohorts. The toxic interaction between mutant LRRK2 and FADD lies downstream of its kinase activity and is required to induce neuronal death. The present study aimed to determine whether the FADD‐LRRK2 interface could be disrupted and what effects this may have on neuroprotection. A series of constrained peptides were designed to mimic the alpha‐helical protein interaction interface between the LRRK2 armadillo region and the death domain of FADD. These peptide‐based protein–protein interaction inhibitors significantly reduced this interaction and blocked apoptotic death of primary neurons expressing G2019S‐LRRK2. This work has identified novel constrained peptides that disrupt the LRRK2‐FADD interface and downregulate mutant LRRK2‐induced neuronal death in an allosteric manner, thereby providing a potential alternative therapeutic approach for PD.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"24 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777243","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}
Sicheng Jiang, Yu Tian, Vlad Nicolaescu, Aslan Mansurov, Glenn Randall, Matthew V. Tirrell, James L. LaBelle
The COVID‐19 pandemic drove a uniquely fervent pursuit to explore the potential of peptide, antibody, protein, and small‐molecule‐based antiviral agents against severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). The interaction between the SARS‐CoV2 spike protein with the angiotensin‐converting enzyme 2 (ACE2) receptor that mediates viral cell entry was a particularly interesting target given its well‐described protein–protein interaction (PPI). This PPI is mediated by an α‐helical portion of ACE2 binding to the receptor binding domain (RBD) of the spike protein and thought to be susceptible to blockade through molecular mimicry. Small numbers of hydrocarbon‐stapled synthetic peptides designed to disrupt or block this interaction were tested individually and were found to have variable efficacy despite having related or overlapping sequences and similarly increased α‐helicity. Reasons for these differences are unclear and reported preclinical successes have been limited. This study sought to better understand reasons for these differences through evaluation of a comprehensive collection of hydrocarbon‐stapled peptides, designed based on four distinct principles: stapling position, number of staples, amino acid sequence, and primary sequence length. Surprisingly, we observed that the helicity and amino acid sequence iterations of hydrocarbon‐stapled peptides did not correlate with their bioactivity. Our results highlight the importance of iterative and combinatorial testing of these compounds to determine a configuration that best mimics natural binding and allows for chain flexibility while sacrificing structural helicity.
{"title":"The Role of Structural Flexibility in Hydrocarbon‐Stapled Peptides Designed to Block Viral Infection via Human ACE2 Mimicry","authors":"Sicheng Jiang, Yu Tian, Vlad Nicolaescu, Aslan Mansurov, Glenn Randall, Matthew V. Tirrell, James L. LaBelle","doi":"10.1002/pep2.24375","DOIUrl":"https://doi.org/10.1002/pep2.24375","url":null,"abstract":"The COVID‐19 pandemic drove a uniquely fervent pursuit to explore the potential of peptide, antibody, protein, and small‐molecule‐based antiviral agents against severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). The interaction between the SARS‐CoV2 spike protein with the angiotensin‐converting enzyme 2 (ACE2) receptor that mediates viral cell entry was a particularly interesting target given its well‐described protein–protein interaction (PPI). This PPI is mediated by an α‐helical portion of ACE2 binding to the receptor binding domain (RBD) of the spike protein and thought to be susceptible to blockade through molecular mimicry. Small numbers of hydrocarbon‐stapled synthetic peptides designed to disrupt or block this interaction were tested individually and were found to have variable efficacy despite having related or overlapping sequences and similarly increased α‐helicity. Reasons for these differences are unclear and reported preclinical successes have been limited. This study sought to better understand reasons for these differences through evaluation of a comprehensive collection of hydrocarbon‐stapled peptides, designed based on four distinct principles: stapling position, number of staples, amino acid sequence, and primary sequence length. Surprisingly, we observed that the helicity and amino acid sequence iterations of hydrocarbon‐stapled peptides did not correlate with their bioactivity. Our results highlight the importance of iterative and combinatorial testing of these compounds to determine a configuration that best mimics natural binding and allows for chain flexibility while sacrificing structural helicity.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"3 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141740307","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}
Dalton Ferreira Matos, Maria Cidinaria Silva Alves, Ruana Carolina Cabral da Silva, Hortência E. P. Santana, Denise Santos Ruzene, Marcus Vinicius de Aragão Batista, Daniel P. Silva
Thaumatin‐like proteins (TLPs) are part of the pathogenesis‐related (PR) proteins that are important in host plant defense. TLPs have multiple defense functions against pathogens (bacteria, viruses, and fungi) and are involved in other biological processes of several living organisms. However, the biological role of TLPs must be elucidated for other species, such as Phaseolus lunatus, popularly known as lima bean. In this study, we propose to investigate the biological activity of TLPs in P. lunatus, which can help develop a detailed functional characterization of the TLP gene in other crop cultures. As a result, a total of 31 PlTPLs genes and 16 highly conserved cysteine residues for each family member were identified in the lima bean genome. Regarding phylogenetic analysis, 128 TLPs from different plant species, including P. lunatus, were used, and the phenetic tree revealed that the TLPs could be divided into six groups. The leading group was Group 4, containing 34 TLPs; the smallest was Group 7, containing only a single TLP. The analysis of antimicrobial and antiviral activity revealed that 27 PlTLPs have antimicrobial activity and 7 PlTLPs have potential antiviral activity. For chromosomal distribution of the PlTLPs, 8 of 11 chromosomes presented at least one PlTLs on one of the chromosomes. Finally, molecular modeling was carried out between two TLPs (PlTLP5 and PlTLP14), which presented antimicrobial and antiviral activity and did not have allergenic activity. The results showed that the two candidates presented ≥90% of their residues in the favorable regions and ∼10% in the permitted regions, demonstrating that the two PlTLPs are considered promising targets for biotechnological applications, especially those related to the genetic improvement of agricultural crops and the development of antimicrobial agents.
{"title":"In Silico Structural and Functional Characterization of the Thaumatin‐Like Gene Family in Phaseolus lunatus Reveals the Potential for Microbial and Antiviral Activity","authors":"Dalton Ferreira Matos, Maria Cidinaria Silva Alves, Ruana Carolina Cabral da Silva, Hortência E. P. Santana, Denise Santos Ruzene, Marcus Vinicius de Aragão Batista, Daniel P. Silva","doi":"10.1002/pep2.24373","DOIUrl":"https://doi.org/10.1002/pep2.24373","url":null,"abstract":"Thaumatin‐like proteins (TLPs) are part of the pathogenesis‐related (PR) proteins that are important in host plant defense. TLPs have multiple defense functions against pathogens (bacteria, viruses, and fungi) and are involved in other biological processes of several living organisms. However, the biological role of TLPs must be elucidated for other species, such as <jats:italic>Phaseolus lunatus</jats:italic>, popularly known as lima bean. In this study, we propose to investigate the biological activity of TLPs in <jats:italic>P. lunatus</jats:italic>, which can help develop a detailed functional characterization of the <jats:italic>TLP</jats:italic> gene in other crop cultures. As a result, a total of 31 <jats:italic>PlTPLs</jats:italic> genes and 16 highly conserved cysteine residues for each family member were identified in the lima bean genome. Regarding phylogenetic analysis, 128 TLPs from different plant species, including <jats:italic>P. lunatus</jats:italic>, were used, and the phenetic tree revealed that the TLPs could be divided into six groups. The leading group was Group 4, containing 34 TLPs; the smallest was Group 7, containing only a single TLP. The analysis of antimicrobial and antiviral activity revealed that 27 PlTLPs have antimicrobial activity and 7 PlTLPs have potential antiviral activity. For chromosomal distribution of the <jats:italic>PlTLPs</jats:italic>, 8 of 11 chromosomes presented at least one <jats:italic>PlTLs</jats:italic> on one of the chromosomes. Finally, molecular modeling was carried out between two TLPs (PlTLP5 and PlTLP14), which presented antimicrobial and antiviral activity and did not have allergenic activity. The results showed that the two candidates presented ≥90% of their residues in the favorable regions and ∼10% in the permitted regions, demonstrating that the two PlTLPs are considered promising targets for biotechnological applications, especially those related to the genetic improvement of agricultural crops and the development of antimicrobial agents.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"25 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141739793","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}
Breast cancer ranks as a leading cause of mortality, primarily affecting females. With the reported side effects of conventional anticancer drugs, herbal sources have emerged as an effective alternative for the treatment of various severe diseases like cancer. Hydrocotyle javanica Thunb. (H. javanica) is a perennial herb belonging to Araliaceae family. This study explored the ethnobotanical use of H. javanica, its pharmacognosy, antioxidant, and phytochemical characterization using liquid chromatography‐mass spectrometry tool, and molecular docking against breast cancer receptor, human epidermal growth factor receptor‐2 (HER2). The study revealed morphological, microscopic diagnostic features, and physicochemical properties of H. javanica. Methanolic extract of H. javanica (MEHJ) displayed dose‐dependent antioxidant activities. LC–MS analysis characterized metabolites of flavonoids, phenolic acids, triterpenoid, and triterpenoid saponin. Phytochemicals including chlorogenic acid, astragalin, and hyperoside, displayed the most favorable binding affinity with HER2 during molecular docking. These phytochemicals also possessed significant drug‐likeness characteristics. Furthermore, molecular dynamic simulation demonstrated stable interaction between these phytochemicals and HER2, suggesting a potential inhibitor of HER2, a crucial target in breast cancer treatment. Therefore, the present study offers an opportunity for further research and development of anticancer drugs derived from H. javanica.
乳腺癌是导致死亡的主要原因之一，主要影响女性。由于传统抗癌药物的副作用，草药已成为治疗癌症等各种严重疾病的有效替代品。Hydrocotyle javanica Thunb.（H. javanica）是一种属于旱金莲科的多年生草本植物。本研究探讨了 H. javanica 的民族植物学用途、其药理、抗氧化和植物化学特征，使用了液相色谱-质谱工具，并针对乳腺癌受体、人表皮生长因子受体-2（HER2）进行了分子对接。该研究揭示了 H. javanica 的形态、显微诊断特征和理化性质。H. javanica的甲醇提取物（MEHJ）显示出剂量依赖性抗氧化活性。LC-MS 分析表征了黄酮类、酚酸类、三萜类和三萜皂苷等代谢物。在分子对接过程中，绿原酸、黄芪苷和金丝桃苷等植物化学物质与 HER2 的结合亲和力最强。这些植物化学物质还具有显著的药物相似性特征。此外，分子动态模拟显示这些植物化学物质与 HER2 之间存在稳定的相互作用，这表明这些植物化学物质可能是乳腺癌治疗的关键靶点 HER2 的潜在抑制剂。因此，本研究为进一步研究和开发来自爪哇的抗癌药物提供了机会。
{"title":"Integrated Pharmacognostic and Computational Analysis of Hydrocotyle javanica Thunb. Phytochemicals as a Potential HER2 Tyrosine Kinase Inhibitor in Breast Cancer","authors":"Anjini Bellai, Satyendra Deka, Hui Tag, Kunal Bhattacharya, Pallabi Kalita Hui","doi":"10.1002/pep2.24372","DOIUrl":"https://doi.org/10.1002/pep2.24372","url":null,"abstract":"Breast cancer ranks as a leading cause of mortality, primarily affecting females. With the reported side effects of conventional anticancer drugs, herbal sources have emerged as an effective alternative for the treatment of various severe diseases like cancer. <jats:italic>Hydrocotyle javanica</jats:italic> Thunb. (<jats:italic>H. javanica</jats:italic>) is a perennial herb belonging to Araliaceae family. This study explored the ethnobotanical use of <jats:italic>H. javanica</jats:italic>, its pharmacognosy, antioxidant, and phytochemical characterization using liquid chromatography‐mass spectrometry tool, and molecular docking against breast cancer receptor, human epidermal growth factor receptor‐2 (HER2). The study revealed morphological, microscopic diagnostic features, and physicochemical properties of <jats:italic>H. javanica</jats:italic>. Methanolic extract of <jats:italic>H. javanica</jats:italic> (MEHJ) displayed dose‐dependent antioxidant activities. LC–MS analysis characterized metabolites of flavonoids, phenolic acids, triterpenoid, and triterpenoid saponin. Phytochemicals including chlorogenic acid, astragalin, and hyperoside, displayed the most favorable binding affinity with HER2 during molecular docking. These phytochemicals also possessed significant drug‐likeness characteristics. Furthermore, molecular dynamic simulation demonstrated stable interaction between these phytochemicals and HER2, suggesting a potential inhibitor of HER2, a crucial target in breast cancer treatment. Therefore, the present study offers an opportunity for further research and development of anticancer drugs derived from <jats:italic>H. javanica.</jats:italic>","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"22 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141609932","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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