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A Rational Approach for Creating Peptides Mimicking Antibody Binding.


ABSTRACT: This study reports a novel method to design peptides that mimic antibody binding. Using the Knob-Socket model for protein-protein interaction, the interaction surface between Cetuximab and EGFR was mapped. EGFR binding peptides were designed based on geometry and the probability of the mapped knob-sockets pairs. Designed peptides were synthesized and then characterized for binding specificity, affinity, cytotoxicity of drug-peptide conjugate and inhibition of phosphorylation. In cell culture studies, designed peptides specifically bind and internalize to EGFR overexpressing cells with three to four-fold higher uptake compared to control cells that do not overexpress EGFR. The designed peptide, Pep11, bound to EGFR with KD of 252?nM. Cytotoxicity of Monomethyl Auristatin E (MMAE)-EGFR-Pep11 peptide-drug conjugate was more than 2,000 fold higher against EGFR overexpressing cell lines A431, MDA MB 468 than control HEK 293 cells which lack EGFR overexpression. MMAE-EGFR-Pep11 conjugate also showed more than 90-fold lower cytotoxicity towards non-EGFR overexpressing HEK 293 cells when compared with cytotoxicity of MMAE itself. In conclusion, a method that can rationally design peptides using knob-socket model is presented. This method was successfully applied to create peptides based on the antigen-antibody interaction to mimic the specificity, affinity and functionality of antibody.

SUBMITTER: Sachdeva S 

PROVIDER: S-EPMC6353898 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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A Rational Approach for Creating Peptides Mimicking Antibody Binding.

Sachdeva Sameer S   Joo Hyun H   Tsai Jerry J   Jasti Bhaskara B   Li Xiaoling X  

Scientific reports 20190130 1


This study reports a novel method to design peptides that mimic antibody binding. Using the Knob-Socket model for protein-protein interaction, the interaction surface between Cetuximab and EGFR was mapped. EGFR binding peptides were designed based on geometry and the probability of the mapped knob-sockets pairs. Designed peptides were synthesized and then characterized for binding specificity, affinity, cytotoxicity of drug-peptide conjugate and inhibition of phosphorylation. In cell culture stu  ...[more]

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