CHAPTER 10. Chemical Approaches for Localization, Characterization and Mimicry of Peptide Epitopes

Werkhoven, Paul R.; Liskamp, Rob M. J.

doi:10.1039/9781849737159-00263

Cited by 4 publications

(5 citation statements)

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“…pertussis . Although this was a very promising result, we think in order to further improve chances for ultimately a successful synthetic HCV vaccine, we have to mimic neutralizing epitopes present in E2 as closely as possible and ligate them on a diversity of suitable scaffold molecules. − …”

Section: Introductionmentioning

confidence: 99%

“…Conformational constraints are probably very important in the design of epitope mimics, since they can induce or enforce conformations of epitopes as they are present in the native protein . Many epitopes comprise looplike structures, and mimicry of looplike peptide sequences is best achieved by cyclization.…”

Section: Introductionmentioning

confidence: 99%

“…18,19 Conformational constraints are probably very important in the design of epitope mimics, since they can induce or enforce conformations of epitopes as they are present in the native protein. 15 Many epitopes comprise looplike structures, and mimicry of looplike peptide sequences is best achieved by cyclization. Furthermore, introduction of conformational constraints by cyclization has been found to improve rigidity, stability, bioavailability, and biological activity of peptide-based therapeutics.…”

Section: ■ Introductionmentioning

confidence: 99%

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Immobilization by Surface Conjugation of Cyclic Peptides for Effective Mimicry of the HCV-Envelope E2 Protein as a Strategy toward Synthetic Vaccines

et al. 2018

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Mimicry of the binding interface of antibody-antigen interactions using peptide-based modulators (i.e., epitope mimics) has promising applications for vaccine design. These epitope mimics can be synthesized in a streamlined and straightforward fashion, thereby allowing for high-throughput analysis. The design of epitope mimics is highly influenced by their spatial configuration and structural conformation. It is widely assumed that for proper mimicry sufficient conformational constraints have to be implemented. This paper describes the synthesis of bromide derivatives functionalized with a flexible TEG linker equipped with a thiol-moiety that could be used to support cyclic or linear peptides. The cyclic and linear epitope mimics were covalently conjugated via the free thiol-moiety on maleimide-activated plate surfaces. The resulting covalent, uniform, and oriented coated surface of cyclic or linear epitope mimics were subjected to an ELISA to investigate the effect of peptide cyclization with respect to mimicry of an antigen-antibody interaction of the HCV E2 glycoprotein. To the best of our knowledge, the benefit of cyclized peptides over linear peptides has been clearly demonstrated here for the first time. Cyclic epitope mimics, and not the linear epitope mimics, demonstrated specificity toward their monoclonal antibodies HC84.1 and V3.2, respectively. The described strategy for the construction of epitope mimics shows potential for high-throughput screening of key binding residues by simply changing the amino acid sequences within synthetic peptides. In this way, leucine-438 has been identified as a key binding residue for binding monoclonal antibody V3.2.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Immobilization by Surface Conjugation of Cyclic Peptides for Effective Mimicry of the HCV-Envelope E2 Protein as a Strategy toward Synthetic Vaccines

et al. 2018

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“…Instead of only looking towards previously developed strategies to target these new threats that are posed by these viruses, it may be necessary to adopt alternative strategies to develop effective vaccines. One such strategy could be found in mimicry of crucial and exposed viral proteins [ 15 , 16 ]. Conceptually, protein mimicry is based on capitalizing on known peptide sequences (epitopes) within the viral proteins that reduce virus efficacy when targeted and recognized by the antibodies of the immune system.…”

Section: Introductionmentioning

confidence: 99%

“…However, successful mimicry of peptide epitopes does not only depend on synthetic peptides with the correct amino acid sequence. Instead, these epitopes often have complex spatial conformations when present within the viral protein that need to be included in a synthetic vaccine [ 15 , 16 ]. Such conformations can include loops, α-helices, and β-sheet-like structures.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of HCV-E2 Glycoprotein Epitope Mimics in Molecular Construction of Potential Synthetic Vaccines

Meuleman

Cowton

Patel

et al. 2021

Viruses

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Hepatitis C virus remains a global threat, despite the availability of highly effective direct-acting antiviral (DAA) drugs. With thousands of new infections annually, the need for a prophylactic vaccine is evident. However, traditional vaccine design has been unable to provide effective vaccines so far. Therefore, alternative strategies need to be investigated. In this work, a chemistry-based approach is explored towards fully synthetic peptide-based vaccines using epitope mimicry, by focusing on highly effective and conserved amino acid sequences in HCV, which, upon antibody binding, inhibit its bio-activity. Continuous and discontinuous epitope mimics were both chemically synthesized based on the HCV-E2 glycoprotein while using designed fully synthetic cyclic peptides. These cyclic epitope mimics were assembled on an orthogonally protected scaffold. The scaffolded epitope mimics have been assessed in immunization experiments to investigate the elicitation of anti-HCV-E2 glycoprotein antibodies. The neutralizing potential of the elicited antibodies was investigated, representing a first step in employing chemically synthesized epitope mimics as a novel strategy towards vaccine design.

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Medicinal Chemical Biology

Jones

2021

Burger's Medicinal Chemistry and Drug Discovery

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Arguably, the two most important decisions facing drug discovery teams are selecting the target and the therapeutic modality as the focus of their research efforts. This article highlights the recent technical advances in medicinal chemical biology that strongly influence these early, yet centrally important, choices. The article is not meant to be a comprehensive review of all innovations in the area. Examples are chosen that illustrate the impact chemical biology has had recently on drug discovery research. Medicinal chemical biology is ideally suited to expand druggable space through the development of target identification and validation technologies. Equally, innovative therapeutic modalities are required to enhance the medicinal toolkit to ensure that high‐quality clinical candidates are delivered that effectively target pathogenesis. Opportunities and challenges are described that serve to inspire further therapeutic research at the chemistry–biology interface.

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CHAPTER 10. Chemical Approaches for Localization, Characterization and Mimicry of Peptide Epitopes

Cited by 4 publications

References 0 publications

Immobilization by Surface Conjugation of Cyclic Peptides for Effective Mimicry of the HCV-Envelope E2 Protein as a Strategy toward Synthetic Vaccines

Immobilization by Surface Conjugation of Cyclic Peptides for Effective Mimicry of the HCV-Envelope E2 Protein as a Strategy toward Synthetic Vaccines

Design and Synthesis of HCV-E2 Glycoprotein Epitope Mimics in Molecular Construction of Potential Synthetic Vaccines

Medicinal Chemical Biology

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