Design, synthesis and evaluation of β-lactam antigenic peptide hybrids; unusual opening of the β-lactam ring in acidic media

Tarbe, Marion; Azcune, Itxaso; Balentová, Eva; Miles, John J.; Edwards, Emily S.J.; Miles, Kim; Do, Priscilla; Baker, Brian M.; Sewell, Andrew K.; Aizpurua, J. M.; Douat, Céline; Quideau, Stéphane

doi:10.1039/c003877f

Cited by 8 publications

(4 citation statements)

References 45 publications

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“…13 In β-lactams 4, such a trajectory is hindered by the α-substituents at both sides of the 2-azetidinone plane, thus making the ring-opening reaction more difficult with respect to other α-monosubstituted β-lactam analogues. 14 Recently, the surprisingly high "amidicity" of monocyclic β-lactams has also been invoked to account for their chemical stability. 15 As mentioned above, only the solution conformation of short β-lactam pseudopeptides containing a central -(β-lactam)-(Gly)-core has been studied so far, and the possible β-turn stabilizing (or destabilizing) effect exerted by the chiral αamino acid residues neighboring the β-lactam nucleus remains to be explored.…”

Section: ■ Introductionmentioning

confidence: 99%

“…This transformation usually involves an Ad N nucleophilic attack onto the CO sp 2 carbon atom following the Bürgi–Dunitz trajectory . In β-lactams 4 , such a trajectory is hindered by the α-substituents at both sides of the 2-azetidinone plane, thus making the ring-opening reaction more difficult with respect to other α-monosubstituted β-lactam analogues . Recently, the surprisingly high “amidicity” of monocyclic β-lactams has also been invoked to account for their chemical stability …”

Section: Introductionmentioning

confidence: 99%

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Chirality-Driven Folding of Short β-Lactam Pseudopeptides

et al. 2012

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Novel enantiopure pseudopeptide models containing a central -(-lactam)-(Aa)-scaffold characterized by the combined presence of an -alkyl--amino--lactam (i+1) residue and a -substituted (i + 2) amino acid have been readily synthesized from -alkyl serines. The conformational analysis of such -lactam pseudopeptides conducted in CDCl3 and DMSO-d6 solutions using 1D-and 2D-NMR techniques revealed an equilibrium between -II turn and -turn conformers, which was ultimately modulated by the relative configuration of the -(-lactam)-(Aa)-residues. Long-range chiral effects on the -lactam pseudopeptide conformers were also found when two (i) and (i + 3) chiral residues were attached to the termini of a central -(-lactam)-(Aib)-segment. In such mimetics, heterochiral (i) and (i + 3) residues reinforced a -II turn conformer, whereas homochiral corner residues stabilized an overlapped -II/ -I double turn motif. No -hairpin nucleation was observed in any instance. In good agreement with the conformers found in solution, -turned and open structures were also characterized by X-ray crystallography. Relative stabilities of the different conformers were estimated computationally at a B3LYP/6-31++G** calculation level, and finally, a conformation equilibrium model based on steric inter-residual interactions around the -(-lactam)-(i + 2)-segment was proposed to account for the observed chiral effects. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 substituted (i+2) amino acid have been readily synthesized from α-alkyl serines. The conformational analysis of such β-lactam pseudopeptides conducted in CDCl 3 and DMSO d6 solutions using 1D and 2D-NMR techniques revealed an equilibrium between β-II turn and γ-turn conformers, which was ultimately modulated by the relative configuration of the -(β-lactam)-(Aa)-residues. Long range chiral effects on the α-lactam pseudopeptide conformers were also found when two (i) and (i+3) chiral residues were attached to the termini of a central -(β-lactam)-(Aib)-segment. In such mimetics, heterochiral (i) and (i+3) residues reinforced a β-II turn conformer, whereas homochiral corner residues stabilized an overlapped β-II/ β-I double turn motif. No β-hairpin nucleation was observed in any instance. In good agreement with the conformers found in solution, β-turned and open structures were also characterized by X-ray crystallography. Relative stabilities of the different conformers were estimated computationally at a B3LYP/6-31++G** calculation level and, finally, a conformation equilibrium model based on steric inter-residual interactions around the -(β-lactam)-(i+2)-segment was proposed to account for the observed chiral effects.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chirality-Driven Folding of Short β-Lactam Pseudopeptides

et al. 2012

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“…Like the studies that covalently combined conventional antibiotics and small molecules, we undertook to prepare similar conjugates of 7‐ACA and 7‐ADCA with AMPs via SPPS. In general, beta‐lactam rings are not resistant to the final acidic cleavage conditions of SPPS . However, the total synthesis of cephalosporin showed the stability of its β‐lactam ring in presence of TFA .…”

Section: Resultsmentioning

confidence: 99%

Covalent conjugation of cationic antimicrobial peptides with a β‐lactam antibiotic core

O'Brien-Simpson

Holden

et al. 2018

Peptide Science

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To combat the serious issue of increasing global antibiotic resistance, new antimicrobial therapies are urgently required. As one alternative, previously used antibiotics are being investigated for use in combination with more modern antibiotics including antimicrobial peptides. Towards this goal, 7‐aminocephalosporanic acid, the precursor to the conventional β‐lactam antibiotic, cephalosporin, and the related compound, 7‐aminodesacetoxycephalosporanic acid, were each chemically modified to enable their use in solid phase peptide synthesis for covalent conjugation via their 7‐amino group and a glycolic linker to the N‐terminus of a series of cationic antimicrobial peptides, MSI‐78, CA(1‐7)M(2‐9)NH2 and des‐Chex1‐Arg20. Chemically functionalized Cα‐Fm‐protected 7‐aminocephalosporanic acid and 7‐aminodesacetoxycephalosporanic acid building blocks were separately prepared and attached by their 7‐amino group to the N‐terminus of each peptide on the solid phase via a glutaric anhydride linker. The resulting conjugated AMPs were assessed for antibacterial activity against a panel of six Gram‐negative bacteria, including clinically isolated multi‐drug resistant (MDR) pathogens. Only the conjugated MSI‐78 analogues displayed significant activity against Acinetobacter baumannii and MDR A. baumannii 156 and enhanced activity against Klebsiella pneumoniae. Further work is required to optimize the conjugation of AMPs to 7‐cephalosporanic acid and/or 7‐aminodesacetoxycephalosporanic acid to universally induce an enhanced effect on killing of drug sensitive and MDR bacterial strains that are common causes of hospital‐acquired infections.

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“…While the peptide bond modification was deleterious, using modified amino acids such as α-methylated, N-hydroxylated or β-amino acids was efficient to protect against proteolysis while retaining the peptide antigenicity. Later, the central part of this peptide, the TCR-contacting portion, was successfully modified by a nonpeptidic moiety to increase its activity [ 87 , 88 ]. A derivative with an indole acetic acid sidechain resulted in an increased T cell response.…”

Section: How To Improve the Peptide?mentioning

confidence: 99%

Peptide Vaccines in Melanoma: Chemical Approaches towards Improved Immunotherapeutic Efficacy

Bánóczi

Szabó

2023

Pharmaceutics

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Cancer of the skin is by far the most common of all cancers. Although the incidence of melanoma is relatively low among skin cancers, it can account for a high number of skin cancer deaths. Since the start of deeper insight into the mechanisms of melanoma tumorigenesis and their strong interaction with the immune system, the development of new therapeutical strategies has been continuously rising. The high number of melanoma cell mutations provides a diverse set of antigens that the immune system can recognize and use to distinguish tumor cells from normal cells. Peptide-based synthetic anti-tumor vaccines are based on tumor antigens that elicit an immune response due to antigen-presenting cells (APCs). Although targeting APCs with peptide antigens is the most important assumption for vaccine development, peptide antigens alone are poorly immunogenic. The immunogenicity of peptide antigens can be improved not only by synthetic modifications but also by the assistance of adjuvants and/or delivery systems. The current review summarizes the different chemical approaches for the development of effective peptide-based vaccines for the immunotherapeutic treatment of advanced melanoma.

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Design, synthesis and evaluation of β-lactam antigenic peptide hybrids; unusual opening of the β-lactam ring in acidic media

Cited by 8 publications

References 45 publications

Chirality-Driven Folding of Short β-Lactam Pseudopeptides

Chirality-Driven Folding of Short β-Lactam Pseudopeptides

Covalent conjugation of cationic antimicrobial peptides with a β‐lactam antibiotic core

Peptide Vaccines in Melanoma: Chemical Approaches towards Improved Immunotherapeutic Efficacy

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