In this study we present the design and synthesis of a novel class of peptidomimetics, the β(3R3)... more In this study we present the design and synthesis of a novel class of peptidomimetics, the β(3R3)-peptides. Via alternating directions of the amide bonds along β-peptide sequences, β(3R3)-peptides can potentially extend the structural space available to β-peptidic foldamers. Detailed analysis at the air-water interface shows strand conformations and the formation of sheet assemblies with different degrees of crystallinity. Furthermore β(3R3)-peptides exhibit a high proteolytic stability thus making them an interesting new class of peptidomimetics for biomedical applications.
We introduce a novel class of membrane active peptidomimetics, the amphiphilic cationic β-peptide... more We introduce a novel class of membrane active peptidomimetics, the amphiphilic cationic β-peptides, and evaluate their potential as antimicrobial agents. The design criteria, the building block and oligomer synthesis as well as a detailed structure−activity relationship (SAR) study are reported. Specifically, infrared reflection absorption spectroscopy (IRRAS) was employed to investigate structural features of amphiphilic cationic β-peptide sequences at the hydrophobic/hydrophilic air/ liquid interface. Furthermore, Langmuir monolayers of anionic and zwitterionic phospholipids have been used to model the interactions of amphiphilic cationic β-peptides with prokaryotic and eukaryotic cellular membranes in order to predict their membrane selectivity and elucidate their mechanism of action. Lastly, antimicrobial activity was tested against Gram-positive M. luteus and S. aureus as well as against Gram-negative E. coli and P. aeruginosa bacteria along with testing hemolytic activity and ...
Many biological functions at cell level are mediated by the glycocalyx, a dense carbohydrate-pres... more Many biological functions at cell level are mediated by the glycocalyx, a dense carbohydrate-presenting layer. In this layer specific interactions between carbohydrate ligands and protein receptors are formed to control cell–cell recognition, cell adhesion and related processes. The aim of this work is to shed light on the principles of complex formation between surface anchored carbohydrates and receptor surfaces by measuring the specific adhesion between surface bound mannose on a concanavalin A (ConA) layer via poly(ethylene glycol)-(PEG)-based soft colloidal probes (SCPs). Special emphasis is on the dependence of multivalent presentation and density of carbohydrate units on specific adhesion. Consequently, we first present a synthetic strategy that allows for controlled density variation of functional groups on the PEG scaffold using unsaturated carboxylic acids (crotonic acid, acrylic acid, methacrylic acid) as grafting units for mannose conjugation. We showed by a range of ana...
The synthesis of monodisperse polymers with a defined monomer sequence is a new challenge in poly... more The synthesis of monodisperse polymers with a defined monomer sequence is a new challenge in polymer chemistry. Recently, we introduced a novel synthetic strategy towards monodisperse, sequence‐defined poly(amidoamine)s based on the stepwise assembly of diamine and diacid building blocks on a solid support. Here we introduce the first chiral building block suitable for the automated poly(amidoamine) synthesis. The synthetic strategy utilizes natural amino acids as starting materials, thus providing a variety of chiral building blocks with different functionalities in the side chain. As a first chiral monomer, L‐alanine is transformed into a mono Fmoc‐protected diamine building block and successfully introduced into poly(amide) segments. magnified image
Synthetic glycooligomers have emerged as valuable analogues for multivalent glycan structures in ... more Synthetic glycooligomers have emerged as valuable analogues for multivalent glycan structures in nature. These multivalent carbohydrates bind to specific receptors and play a key role in biological processes. In this work, we investigate the specific interaction between mannose ligand presenting soft colloidal probes (SCPs) attached to an atomic force microscope (AFM) cantilever and a Concanavalin A (ConA) receptor surface in the presence of competing glycooligomer ligands. We studied the SCP-ConA adhesion energy via the JKR approach and AFM pull-off experiments in combination with optical microscopy allowing for simultaneous determination of the contact area between SCP and ConA surface. We varied the contact time, loading rate and loading force and measured the resulting mannose/ConA interaction. The average adhesion energy per mannose ligand on the probe was 5 kJ/mol, suggesting that a fraction of mannose ligands presented on the SCP bound to the receptor surface. Adhesion measurements via competitive binding of the SCP in the presence of multivalent glycooligomer ligands did not indicate an influence of their multivalency on the glycooligomer displacement from the ConA surface. The absence of this "multivalency effect" indicates that glycooligomers and ConA do not associate via chelate complexes and shows that steric shielding by the glycooligomers does not slow their displacement upon competitive binding of a ligand presenting surface. These results highlight the high reversibility of carbohydrate-surface interactions, which could be an essential feature of recognition processes on the cell surface.
We introduce a novel class of membrane active peptidomimetics, the amphiphilic cationic β(3R3)-pe... more We introduce a novel class of membrane active peptidomimetics, the amphiphilic cationic β(3R3)-peptides, and evaluate their potential as antimicrobial agents. The design criteria, the building block and oligomer synthesis as well as a detailed structure-activity relationship (SAR) study are reported. Specifically, infrared reflection absorption spectroscopy (IRRAS) was employed to investigate structural features of amphiphilic cationic β(3R3)-peptide sequences at the hydrophobic/hydrophilic air/liquid interface. Furthermore, Langmuir monolayers of anionic and zwitterionic phospholipids have been used to model the interactions of amphiphilic cationic β(3R3)-peptides with prokaryotic and eukaryotic cellular membranes in order to predict their membrane selectivity and elucidate their mechanism of action. Lastly, antimicrobial activity was tested against Gram-positive M. luteus and S. aureus as well as against Gram-negative E. coli and P. aeruginosa bacteria along with testing hemolytic activity and cytotoxicity. We found that amphiphilic cationic β(3R3)-peptide sequences combine high and selective antimicrobial activity with exceptionally low cytotoxicity in comparison to values reported in the literature. Overall, this study provides further insights into the SAR of antimicrobial peptides and peptidomimetics and indicates that amphiphilic cationic β(3R3)-peptides are strong candidates for further development as antimicrobial agents with high therapeutic index.
In this study we present the design and synthesis of a novel class of peptidomimetics, the β(3R3)... more In this study we present the design and synthesis of a novel class of peptidomimetics, the β(3R3)-peptides. Via alternating directions of the amide bonds along β-peptide sequences, β(3R3)-peptides can potentially extend the structural space available to β-peptidic foldamers. Detailed analysis at the air-water interface shows strand conformations and the formation of sheet assemblies with different degrees of crystallinity. Furthermore β(3R3)-peptides exhibit a high proteolytic stability thus making them an interesting new class of peptidomimetics for biomedical applications.
We introduce a novel class of membrane active peptidomimetics, the amphiphilic cationic β-peptide... more We introduce a novel class of membrane active peptidomimetics, the amphiphilic cationic β-peptides, and evaluate their potential as antimicrobial agents. The design criteria, the building block and oligomer synthesis as well as a detailed structure−activity relationship (SAR) study are reported. Specifically, infrared reflection absorption spectroscopy (IRRAS) was employed to investigate structural features of amphiphilic cationic β-peptide sequences at the hydrophobic/hydrophilic air/ liquid interface. Furthermore, Langmuir monolayers of anionic and zwitterionic phospholipids have been used to model the interactions of amphiphilic cationic β-peptides with prokaryotic and eukaryotic cellular membranes in order to predict their membrane selectivity and elucidate their mechanism of action. Lastly, antimicrobial activity was tested against Gram-positive M. luteus and S. aureus as well as against Gram-negative E. coli and P. aeruginosa bacteria along with testing hemolytic activity and ...
Many biological functions at cell level are mediated by the glycocalyx, a dense carbohydrate-pres... more Many biological functions at cell level are mediated by the glycocalyx, a dense carbohydrate-presenting layer. In this layer specific interactions between carbohydrate ligands and protein receptors are formed to control cell–cell recognition, cell adhesion and related processes. The aim of this work is to shed light on the principles of complex formation between surface anchored carbohydrates and receptor surfaces by measuring the specific adhesion between surface bound mannose on a concanavalin A (ConA) layer via poly(ethylene glycol)-(PEG)-based soft colloidal probes (SCPs). Special emphasis is on the dependence of multivalent presentation and density of carbohydrate units on specific adhesion. Consequently, we first present a synthetic strategy that allows for controlled density variation of functional groups on the PEG scaffold using unsaturated carboxylic acids (crotonic acid, acrylic acid, methacrylic acid) as grafting units for mannose conjugation. We showed by a range of ana...
The synthesis of monodisperse polymers with a defined monomer sequence is a new challenge in poly... more The synthesis of monodisperse polymers with a defined monomer sequence is a new challenge in polymer chemistry. Recently, we introduced a novel synthetic strategy towards monodisperse, sequence‐defined poly(amidoamine)s based on the stepwise assembly of diamine and diacid building blocks on a solid support. Here we introduce the first chiral building block suitable for the automated poly(amidoamine) synthesis. The synthetic strategy utilizes natural amino acids as starting materials, thus providing a variety of chiral building blocks with different functionalities in the side chain. As a first chiral monomer, L‐alanine is transformed into a mono Fmoc‐protected diamine building block and successfully introduced into poly(amide) segments. magnified image
Synthetic glycooligomers have emerged as valuable analogues for multivalent glycan structures in ... more Synthetic glycooligomers have emerged as valuable analogues for multivalent glycan structures in nature. These multivalent carbohydrates bind to specific receptors and play a key role in biological processes. In this work, we investigate the specific interaction between mannose ligand presenting soft colloidal probes (SCPs) attached to an atomic force microscope (AFM) cantilever and a Concanavalin A (ConA) receptor surface in the presence of competing glycooligomer ligands. We studied the SCP-ConA adhesion energy via the JKR approach and AFM pull-off experiments in combination with optical microscopy allowing for simultaneous determination of the contact area between SCP and ConA surface. We varied the contact time, loading rate and loading force and measured the resulting mannose/ConA interaction. The average adhesion energy per mannose ligand on the probe was 5 kJ/mol, suggesting that a fraction of mannose ligands presented on the SCP bound to the receptor surface. Adhesion measurements via competitive binding of the SCP in the presence of multivalent glycooligomer ligands did not indicate an influence of their multivalency on the glycooligomer displacement from the ConA surface. The absence of this "multivalency effect" indicates that glycooligomers and ConA do not associate via chelate complexes and shows that steric shielding by the glycooligomers does not slow their displacement upon competitive binding of a ligand presenting surface. These results highlight the high reversibility of carbohydrate-surface interactions, which could be an essential feature of recognition processes on the cell surface.
We introduce a novel class of membrane active peptidomimetics, the amphiphilic cationic β(3R3)-pe... more We introduce a novel class of membrane active peptidomimetics, the amphiphilic cationic β(3R3)-peptides, and evaluate their potential as antimicrobial agents. The design criteria, the building block and oligomer synthesis as well as a detailed structure-activity relationship (SAR) study are reported. Specifically, infrared reflection absorption spectroscopy (IRRAS) was employed to investigate structural features of amphiphilic cationic β(3R3)-peptide sequences at the hydrophobic/hydrophilic air/liquid interface. Furthermore, Langmuir monolayers of anionic and zwitterionic phospholipids have been used to model the interactions of amphiphilic cationic β(3R3)-peptides with prokaryotic and eukaryotic cellular membranes in order to predict their membrane selectivity and elucidate their mechanism of action. Lastly, antimicrobial activity was tested against Gram-positive M. luteus and S. aureus as well as against Gram-negative E. coli and P. aeruginosa bacteria along with testing hemolytic activity and cytotoxicity. We found that amphiphilic cationic β(3R3)-peptide sequences combine high and selective antimicrobial activity with exceptionally low cytotoxicity in comparison to values reported in the literature. Overall, this study provides further insights into the SAR of antimicrobial peptides and peptidomimetics and indicates that amphiphilic cationic β(3R3)-peptides are strong candidates for further development as antimicrobial agents with high therapeutic index.
Uploads
Papers by Simone Mosca