Blood‐brain barrier peptides (BBPs) play a promising role in current drug study of central nervous system diseases. Hence, it is an urgent need to rapidly and accurately discriminating BBPs from non‐BBPs. Experimental approaches are the first choice, however, these methods are expensive and take a lot of time. Thus, more and more researchers focused their attention on computational models. In current work, we developed a support vector machine (SVM) based model to identify BBPs. First, amino acids physicochemical properties were employed to represent peptide sequences, and Pearson's correlation coefficient (PCC) and maximal information coefficient (MIC) were applied to extract useful information. Then, similarity network fusion algorithm was utilized to integrate these two different kinds of features. Next, Fisher algorithm was used to pick out the discriminative features. Finally, these selected features were input into SVM for distinguishing BBPs from non‐BBPs. The proposed model achieved 100.00% and 89.47% classification accuracies on training and independent datasets, respectively. Additionally, we found that pK2 (NH3) property of amino acid plays a key role in discriminating BBPs from non‐BBPs. The results showed that our proposed method is effective, and achieved a significantly improvement in identifying BBPs, as compared with the state‐of‐the‐art approach. The Matlab codes and datasets are freely available at https://figshare.com/articles/online_resource/iBBPs_zip/14723766.
{"title":"Identifying blood‐brain barrier peptides by using amino acids physicochemical properties and features fusion method","authors":"Hongliang Zou","doi":"10.1002/pep2.24247","DOIUrl":"https://doi.org/10.1002/pep2.24247","url":null,"abstract":"Blood‐brain barrier peptides (BBPs) play a promising role in current drug study of central nervous system diseases. Hence, it is an urgent need to rapidly and accurately discriminating BBPs from non‐BBPs. Experimental approaches are the first choice, however, these methods are expensive and take a lot of time. Thus, more and more researchers focused their attention on computational models. In current work, we developed a support vector machine (SVM) based model to identify BBPs. First, amino acids physicochemical properties were employed to represent peptide sequences, and Pearson's correlation coefficient (PCC) and maximal information coefficient (MIC) were applied to extract useful information. Then, similarity network fusion algorithm was utilized to integrate these two different kinds of features. Next, Fisher algorithm was used to pick out the discriminative features. Finally, these selected features were input into SVM for distinguishing BBPs from non‐BBPs. The proposed model achieved 100.00% and 89.47% classification accuracies on training and independent datasets, respectively. Additionally, we found that pK2 (NH3) property of amino acid plays a key role in discriminating BBPs from non‐BBPs. The results showed that our proposed method is effective, and achieved a significantly improvement in identifying BBPs, as compared with the state‐of‐the‐art approach. The Matlab codes and datasets are freely available at https://figshare.com/articles/online_resource/iBBPs_zip/14723766.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":" ","pages":""},"PeriodicalIF":2.4,"publicationDate":"2021-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43903161","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}
We need new treatment options to control bacterial infections. Bacteria use several strategies to resist drug treatment, including modification of the drug target, and adaptation to a different lifestyle, such as intracellular niches within host cells. Drugs that act on diverse targets are less likely to induce resistance in bacteria, than current antibiotics acting on a single molecular target. Antimicrobial peptides have been explored as a new class of antibiotics because they selectively kill bacteria via a mechanism that involves recognition of the negatively charged microbial surface. Furthermore, antimicrobial peptides with cell‐penetrating properties can cross host cell membranes and target bacteria in the cytosol or sequestered in vesicles. Therefore, bacteria in intracellular niches are less capable of evading treatment and the likelihood of establishing drug resistance is further reduced. This review highlights the potential of antimicrobial peptides as alternative therapeutics to target bacterial pathogens in both extracellular and intracellular environments, and to avoid acquired drug‐resistance.
{"title":"Antimicrobial peptides provide wider coverage for targeting drug‐resistant bacterial pathogens","authors":"Anna S. Amiss, S. Henriques, N. Lawrence","doi":"10.1002/pep2.24246","DOIUrl":"https://doi.org/10.1002/pep2.24246","url":null,"abstract":"We need new treatment options to control bacterial infections. Bacteria use several strategies to resist drug treatment, including modification of the drug target, and adaptation to a different lifestyle, such as intracellular niches within host cells. Drugs that act on diverse targets are less likely to induce resistance in bacteria, than current antibiotics acting on a single molecular target. Antimicrobial peptides have been explored as a new class of antibiotics because they selectively kill bacteria via a mechanism that involves recognition of the negatively charged microbial surface. Furthermore, antimicrobial peptides with cell‐penetrating properties can cross host cell membranes and target bacteria in the cytosol or sequestered in vesicles. Therefore, bacteria in intracellular niches are less capable of evading treatment and the likelihood of establishing drug resistance is further reduced. This review highlights the potential of antimicrobial peptides as alternative therapeutics to target bacterial pathogens in both extracellular and intracellular environments, and to avoid acquired drug‐resistance.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":" ","pages":""},"PeriodicalIF":2.4,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45840893","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}
Hyerim Yoon, Jaeyeon Lee, Philjae Kang, Soo Hyuk Choi
The 11/9‐helix is one of nontraditional helices available to α/β‐peptides with alternating residue types. Several β‐amino acid residues are known to promote 11/9‐helical folding with two types of intramolecular hydrogen bonds. Both β2‐amino acids and β3‐amino acids are common acyclic β‐amino acids that can be regarded as homologs of α‐amino acids with the same side chain group. However, β2‐amimo acids have not been widely used as much as β3‐amino acids partly because β2‐residue is believed to be not as strong as β3‐residue in promoting a distinct conformation. Here we report 11/9‐helical folding of α/β‐peptides that consist of L‐α‐alanine and (S)‐β2‐homoalanine with residue alternation. In addition, circular dichroism study reveals that β2‐homoalanine promotes 11/9‐helical folding more strongly than β3‐homoalanine in polar protic solvent conditions.
{"title":"Promotion of 11/9‐helical folding in α/β‐peptides containing β2‐homoalanine residue","authors":"Hyerim Yoon, Jaeyeon Lee, Philjae Kang, Soo Hyuk Choi","doi":"10.1002/pep2.24244","DOIUrl":"https://doi.org/10.1002/pep2.24244","url":null,"abstract":"The 11/9‐helix is one of nontraditional helices available to α/β‐peptides with alternating residue types. Several β‐amino acid residues are known to promote 11/9‐helical folding with two types of intramolecular hydrogen bonds. Both β2‐amino acids and β3‐amino acids are common acyclic β‐amino acids that can be regarded as homologs of α‐amino acids with the same side chain group. However, β2‐amimo acids have not been widely used as much as β3‐amino acids partly because β2‐residue is believed to be not as strong as β3‐residue in promoting a distinct conformation. Here we report 11/9‐helical folding of α/β‐peptides that consist of L‐α‐alanine and (S)‐β2‐homoalanine with residue alternation. In addition, circular dichroism study reveals that β2‐homoalanine promotes 11/9‐helical folding more strongly than β3‐homoalanine in polar protic solvent conditions.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":"114 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2021-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42226141","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}
N. Santos-Filho, Gabriela Marinho Righetto, Marina Rodrigues Pereira, Julia P. Piccoli, Larissa Mathias Teizen Almeida, Thainá Cristina Leal, I. L. Camargo, E. Cilli
The peptide (p‐BthTX‐I)2 [(KKYRYHLKPFCKK)2] and its analog des‐Lys12,Lys13‐(p‐BthTX‐I)2 [(KKYRYHLKPFC)2] showed activity against bacteria and potential specificity against prokaryotic cells. In this study, we synthesized the peptide des‐Cys11,Lys12,Lys13‐(p‐BthTX‐I)2K [(KKYRYHLKPF)2K] with a Lys instead of a Cys residue in the dimerization step, beginning the SPPS with Fmoc‐Lys(Fmoc)‐OH. This change avoided Cys oxidation, decreasing one step in the original peptide synthesis and obtaining a smaller and more stable peptide. The antimicrobial activity of the peptide des‐Cys11,Lys12,Lys13‐(p‐BthTX‐I)2K was superior to that of the (p‐BthTX‐I)2 peptide against the bacterial strains tested. Additionally, to evaluate the impact of the linker position on peptide dimerization, we synthesized peptide E(p‐BthTX‐I)2 [E(KKYRYHLKPFCKK)2] using Fmoc‐Glu‐OH at the end of the synthesis. This N‐terminal dimeric peptide did not increase the antibacterial activity, indicating that the free N‐terminal is essential for (p‐BthTX‐I)2 activity. Additionally, we observed lower antimicrobial activity by substituting positive and aromatic residues with Ala in the alanine scanning assay, irrespective of the amino acid change, indicating that each amino acid is essential for the mechanism of action of the peptide. Therefore, we demonstrated that the (p‐BthTX‐I)2 analog, which is shorter and synthesized by an easier process leading to a more stable peptide, is the most antibacterial active peptide against multidrug‐resistant bacteria and does not increase hemolysis activity.
{"title":"Effect of C‐terminal and N‐terminal dimerization and alanine scanning on antibacterial activity of the analogs of the peptide p‐BthTX‐I","authors":"N. Santos-Filho, Gabriela Marinho Righetto, Marina Rodrigues Pereira, Julia P. Piccoli, Larissa Mathias Teizen Almeida, Thainá Cristina Leal, I. L. Camargo, E. Cilli","doi":"10.1002/pep2.24243","DOIUrl":"https://doi.org/10.1002/pep2.24243","url":null,"abstract":"The peptide (p‐BthTX‐I)2 [(KKYRYHLKPFCKK)2] and its analog des‐Lys12,Lys13‐(p‐BthTX‐I)2 [(KKYRYHLKPFC)2] showed activity against bacteria and potential specificity against prokaryotic cells. In this study, we synthesized the peptide des‐Cys11,Lys12,Lys13‐(p‐BthTX‐I)2K [(KKYRYHLKPF)2K] with a Lys instead of a Cys residue in the dimerization step, beginning the SPPS with Fmoc‐Lys(Fmoc)‐OH. This change avoided Cys oxidation, decreasing one step in the original peptide synthesis and obtaining a smaller and more stable peptide. The antimicrobial activity of the peptide des‐Cys11,Lys12,Lys13‐(p‐BthTX‐I)2K was superior to that of the (p‐BthTX‐I)2 peptide against the bacterial strains tested. Additionally, to evaluate the impact of the linker position on peptide dimerization, we synthesized peptide E(p‐BthTX‐I)2 [E(KKYRYHLKPFCKK)2] using Fmoc‐Glu‐OH at the end of the synthesis. This N‐terminal dimeric peptide did not increase the antibacterial activity, indicating that the free N‐terminal is essential for (p‐BthTX‐I)2 activity. Additionally, we observed lower antimicrobial activity by substituting positive and aromatic residues with Ala in the alanine scanning assay, irrespective of the amino acid change, indicating that each amino acid is essential for the mechanism of action of the peptide. Therefore, we demonstrated that the (p‐BthTX‐I)2 analog, which is shorter and synthesized by an easier process leading to a more stable peptide, is the most antibacterial active peptide against multidrug‐resistant bacteria and does not increase hemolysis activity.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":" ","pages":""},"PeriodicalIF":2.4,"publicationDate":"2021-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/pep2.24243","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44185625","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}
Metals are important molecules in protein biochemistry, as they are involved in various essential biochemical processes. Inspired by the coordination chemistry of metal‐binding proteins, and to improvise the stability of recognition motifs, here we present the design of hyperstable stapled β‐hairpin with a defined metal‐binding cleft. We achieved this by establishing Trp‐Trp covalent cross‐linking in a long‐chain 16‐residue β‐hairpin scaffold, and incorporating a stereospecific Cys2‐His2 tetrad as the metal‐binding cleft. This water‐soluble peptide showed broad metal‐binding properties, with Cu2+ specificity. Importance of the Cys‐His tetrad in metal ion selectivity was established with Asp/Glu substitutions. We propose that such predefined hyperstable β‐hairpins with recognition motifs are useful versatile tools for developing peptide‐based catalysts, and in biomarker design.
{"title":"De novo design of metal‐binding cleft in a Trp‐Trp stapled thermostable β‐hairpin peptide","authors":"Muralikrishna Lella, R. Mahalakshmi","doi":"10.1002/pep2.24240","DOIUrl":"https://doi.org/10.1002/pep2.24240","url":null,"abstract":"Metals are important molecules in protein biochemistry, as they are involved in various essential biochemical processes. Inspired by the coordination chemistry of metal‐binding proteins, and to improvise the stability of recognition motifs, here we present the design of hyperstable stapled β‐hairpin with a defined metal‐binding cleft. We achieved this by establishing Trp‐Trp covalent cross‐linking in a long‐chain 16‐residue β‐hairpin scaffold, and incorporating a stereospecific Cys2‐His2 tetrad as the metal‐binding cleft. This water‐soluble peptide showed broad metal‐binding properties, with Cu2+ specificity. Importance of the Cys‐His tetrad in metal ion selectivity was established with Asp/Glu substitutions. We propose that such predefined hyperstable β‐hairpins with recognition motifs are useful versatile tools for developing peptide‐based catalysts, and in biomarker design.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":" ","pages":""},"PeriodicalIF":2.4,"publicationDate":"2021-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/pep2.24240","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43194405","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}
E. A. Egorova, G. Gooris, Prianka Luther, J. Bouwstra, A. Kros, A. Boyle
The self‐assembly properties of peptide amphiphiles make them attractive for a range of applications, such as scaffolds for cell culture, drug delivery vehicles, or as stabilizing coatings for nanoparticles. The latter application requires derivatization of the amphiphiles to enable them to bind to, and interact with, a surface. This can be achieved by introduction of a thiol which facilitates binding to gold surfaces for example. However, small changes to the composition of peptide amphiphiles can have a large impact on their self‐assembly behavior. Therefore, we have synthesized and characterized a range of amphiphiles with different peptide sequences, alkyl chain lengths, and with or without a terminal thiol. We have characterized their structure and self‐assembly using circular dichroism (CD) spectroscopy, attenuated total reflection infrared (ATR‐IR) spectroscopy, and transmission electron microscopy (TEM). We discuss how changes to the peptide sequence and alkyl chain affect self‐assembly and compare the self‐assembly properties of thiolated and non‐thiolated amphiphiles. Such knowledge not only provides fundamental insights as to how self‐assembly can be controlled, but will also be helpful in determining which amphiphiles are most suitable for use as stabilizing nanoparticle coatings.
{"title":"Self‐assembly of thiolated versus non‐thiolated peptide amphiphiles","authors":"E. A. Egorova, G. Gooris, Prianka Luther, J. Bouwstra, A. Kros, A. Boyle","doi":"10.1002/pep2.24236","DOIUrl":"https://doi.org/10.1002/pep2.24236","url":null,"abstract":"The self‐assembly properties of peptide amphiphiles make them attractive for a range of applications, such as scaffolds for cell culture, drug delivery vehicles, or as stabilizing coatings for nanoparticles. The latter application requires derivatization of the amphiphiles to enable them to bind to, and interact with, a surface. This can be achieved by introduction of a thiol which facilitates binding to gold surfaces for example. However, small changes to the composition of peptide amphiphiles can have a large impact on their self‐assembly behavior. Therefore, we have synthesized and characterized a range of amphiphiles with different peptide sequences, alkyl chain lengths, and with or without a terminal thiol. We have characterized their structure and self‐assembly using circular dichroism (CD) spectroscopy, attenuated total reflection infrared (ATR‐IR) spectroscopy, and transmission electron microscopy (TEM). We discuss how changes to the peptide sequence and alkyl chain affect self‐assembly and compare the self‐assembly properties of thiolated and non‐thiolated amphiphiles. Such knowledge not only provides fundamental insights as to how self‐assembly can be controlled, but will also be helpful in determining which amphiphiles are most suitable for use as stabilizing nanoparticle coatings.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":" ","pages":""},"PeriodicalIF":2.4,"publicationDate":"2021-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/pep2.24236","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44969402","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}
Soyoung Kim, Ji-Yu Lee, Jieun Choi, H. Nam, Jiwon Seo, Jiyoun Lee
Mitochondria‐targeted delivery methods offer a straightforward approach for studying mitochondria‐related diseases and potentially streamlining therapeutic development. Peptoids (oligo‐N‐substituted glycines) are biocompatible peptidomimetics that display similar physicochemical properties as peptides with the added advantage of enhanced resistance to proteolytic cleavage. In particular, amphipathic peptoids are membrane‐permeable and their cationic charges and hydrophobicity can be readily modified for specific purposes, such as cell penetration, anti‐cancer or antibacterial activity. Previously, we identified a series of amphipathic peptoids that showed efficient cell penetration and mitochondrial localization. As a continued effort to identify selective mitochondrial transporters, we designed new analogs with varying hydrophobicity and net charges. We observed that overall increase in hydrophobicity did not result in enhanced mitochondrial localization while maintaining high cell permeability. Moreover, a certain degree of a positive net charge was critical for mitochondrial localization. In conclusion, our mitochondria‐targeting peptoids provide a highly selective and robust delivery system for bioactive molecules.
{"title":"Synthesis and structure‐activity relationship of mitochondria‐targeting peptoids with varying hydrophobicity and cationic charge","authors":"Soyoung Kim, Ji-Yu Lee, Jieun Choi, H. Nam, Jiwon Seo, Jiyoun Lee","doi":"10.1002/pep2.24239","DOIUrl":"https://doi.org/10.1002/pep2.24239","url":null,"abstract":"Mitochondria‐targeted delivery methods offer a straightforward approach for studying mitochondria‐related diseases and potentially streamlining therapeutic development. Peptoids (oligo‐N‐substituted glycines) are biocompatible peptidomimetics that display similar physicochemical properties as peptides with the added advantage of enhanced resistance to proteolytic cleavage. In particular, amphipathic peptoids are membrane‐permeable and their cationic charges and hydrophobicity can be readily modified for specific purposes, such as cell penetration, anti‐cancer or antibacterial activity. Previously, we identified a series of amphipathic peptoids that showed efficient cell penetration and mitochondrial localization. As a continued effort to identify selective mitochondrial transporters, we designed new analogs with varying hydrophobicity and net charges. We observed that overall increase in hydrophobicity did not result in enhanced mitochondrial localization while maintaining high cell permeability. Moreover, a certain degree of a positive net charge was critical for mitochondrial localization. In conclusion, our mitochondria‐targeting peptoids provide a highly selective and robust delivery system for bioactive molecules.","PeriodicalId":19825,"journal":{"name":"Peptide Science","volume":" ","pages":""},"PeriodicalIF":2.4,"publicationDate":"2021-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/pep2.24239","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44342681","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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