Prevention of passively transferred experimental autoimmune myasthenia gravis by a phage library-derived cyclic peptide

Natarajan, Venkatesh; Im, Sin Hyeog; Balass, Moshe; Fuchs, Sara; Katchalski‐Katzir, Ephraim

doi:10.1073/pnas.97.2.761

Cited by 25 publications

(22 citation statements)

References 29 publications

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“…This finding adds to the knowledge on factors driving peptide selections from phage-display libraries. Such positive influence of the viral environment on the binding properties of phage-expressed peptides has also been reported by others (33,42). Therefore, we postulate that addition of amino acids adjacent to expressed peptides can be viewed as a possible mean to improve their interactions with the receptors used in screening of the phage-display libraries.…”

Section: Discussionsupporting

confidence: 72%

“…The mimicry phenomenon for peptides isolated from phage-display libraries can be investigated on many levels including phage-expressed and free peptides, or peptides fused to proteins (31,32). Finally, characterization of functional (agonist or antagonist activity) or immunological mimicry of peptides can be performed (33,34). We aimed to probe the molecular basis of mAb 14G2a binding by peptides isolated from the LX-8 library.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Analysis and optimization of interactions between peptides mimicking the GD2 ganglioside and the monoclonal antibody 14G2a

Horwacik

Kurciński²,

Bzowska³

et al. 2011

Int J Mol Med

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Abstract. Overexpression of the Gd2 ganglioside (Gd2) is a hallmark of neuroblastoma. The antigen is used in neuroblastoma diagnosis and to target newly developed therapies to cancer cells. Peptide mimetics are novel approaches in the design of antigens for vaccine development. We previously reported the isolation of five GD2-mimicking peptides from the LX-8 phage display library with the monoclonal antibody (mAb) 14G2a. The goal of our current study was to analyze and optimize the binding of the peptide mimetics to the mAb 14G2a. Therefore, we performed further experiments and supported them with molecular modeling to investigate structure-activity relationships that are the basis for the observed mimicry of Gd2 by our peptides. Here, we show that the peptides have overlapping binding sites on the mAb, 14G2a and restricted specificity, as they did not crossreact with other ganglioside-specific antibodies tested. In addition we demonstrate that the phage environment was involved in the process of selection of our peptides. The AAEGd sequence taken from the viral major coat protein, p8, and added to the c-termini of the peptides #65, #85 and #94 significantly improved their binding to the mAb, 14G2a. By application of analogs with amino acid substitutions and sequence truncations, we elucidated the structure-activity relationships necessary for the interactions between the 14G2a mAb and the peptide #94 (RCNPNMEPPRCF). We identified amino acids indispensable for the observed Gd2-mimicry by #94 and confirmed a pivotal role of the disulphide bridge between the cysteine residues of #94 for binding to the mAb 14G2a. More importantly, we report five new peptides demonstrating a significant improvement of mAb 14G2a binding. The experimental data were supported and expanded with molecular modeling tools. Taken together, the experimental results and the in silico data allowed us to probe in detail the mechanism of the molecular mimicry of Gd2 by the peptides. Additionally, we significantly optimized binding of the leading peptide sequence #94 to the mAb 14G2a. We can conclude that our findings add to the knowledge on factors governing selections of peptide mimetics from phage-display libraries.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Analysis and optimization of interactions between peptides mimicking the GD2 ganglioside and the monoclonal antibody 14G2a

Horwacik

Kurciński²,

Bzowska³

et al. 2011

Int J Mol Med

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“…Nevertheless, the structurally constrained peptides are also more stable in bio-fluids, with ends protected from proteases [105,106]. Various examples as well as cyclization strategies have been summarized by Li et al [105].…”

Section: Modifications On the Peptide Backbonementioning

confidence: 99%

Improving the Stability of Aptamers by Chemical Modification

Wang

Wu²,

Niu³

et al. 2011

CMC

145

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Ever since the invention of SELEX (systematic evolution of ligands by exponential enrichment), there has been rapid development for aptamers over the last two decades, making them a promising approach in therapeutic applications as either drug candidates or diagnostic tools. For therapeutic purposes, a durable performance of aptamers in biofluids is required, which is, however, hampered by the lack of stability of most aptamers. Not only are the nucleic acid aptamers susceptible to nucleases, the peptide aptamers are also subjective to degradation by proteases. With the advancement of chemical biology, numerous attempts have been made to overcome this obstacle, many resulting in significant improvements in stability. In this review, chemical modifications to increase the stability of three main types of aptamers, DNA, RNA and peptide are comprehensively summarized. For nucleic acid aptamers, development of modified SELEX coupled with mutated polymerase is discussed, which is adaptive to a number of modifications in aptamers and in a large extent facilitates the research of aptamer-modifications. For peptide aptamers, approaches in molecular biology with introduction of stabilizing protein as well as the switch of scaffold protein are included, which may represent a future direction of chemical conjugations to aptamers.

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“…MG and its animal model, experimental autoimmune myasthenia gravis (EAMG), mainly result from autoantibodies directed against acetylcholine receptors (AChR) in the postsynaptic muscle membrane [42]. Anti-AChR Fab fragments and peptide mimotopes of AChR have been developed to block interaction of the antibodies with the receptors in MG [43,44]. Lee and Sullenger developed an 89-mer nuclease-resistant RNA aptamer with 2¢-amino pyrimidines that bound both the rat monoclonal antibody (mAb198) against human AChR and patient autoantibodies.…”

Section: Aptamers For Mgmentioning

confidence: 99%

Aptamer Oligonucleotides: Novel Potential Therapeutic Agents in Autoimmune Disease

Lan

2015

Nucleic Acid Therapeutics

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Aptamers are single-stranded deoxyribonucleic acid or ribonucleic acid oligonucleotides generated in vitro based on affinity for certain target molecules by a process known as Systematic Evolution of Ligands by Exponential Enrichment. Aptamers can bind their target molecules with high specificity and selectivity by means of structure compatibility, stacking of aromatic rings, electrostatic and van der Waals interactions, and hydrogen bonding. With several advantages over monoclonal antibodies and other conventional small-molecule therapeutics, such as high specificity and affinity, negligible batch to batch variation, flexible modification and stability, lack of toxicity and low immunogenicity, aptamers are becoming promising novel diagnostic and therapeutic agents. This review focuses on the development of aptamers as potential therapeutics for autoimmune diseases, including diabetes mellitus, multiple sclerosis, rheumatoid arthritis, myasthenia gravis, and systemic lupus erythematosus.

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Prevention of passively transferred experimental autoimmune myasthenia gravis by a phage library-derived cyclic peptide

Cited by 25 publications

References 29 publications

Analysis and optimization of interactions between peptides mimicking the GD2 ganglioside and the monoclonal antibody 14G2a

Analysis and optimization of interactions between peptides mimicking the GD2 ganglioside and the monoclonal antibody 14G2a

Improving the Stability of Aptamers by Chemical Modification

Aptamer Oligonucleotides: Novel Potential Therapeutic Agents in Autoimmune Disease

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