A Rational Approach for Creating Peptides Mimicking Antibody Binding
| Autor: | Sameer Sachdeva, Xiaoling Li, Bhaskara R. Jasti, Jerry Tsai, Hyun Joo |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cell Survival Amino Acid Motifs lcsh:Medicine Peptide Plasma protein binding Article Protein Structure Secondary 03 medical and health sciences chemistry.chemical_compound Drug Delivery Systems 0302 clinical medicine Cell Line Tumor Humans Phosphorylation Cytotoxicity lcsh:Science Binding selectivity chemistry.chemical_classification Multidisciplinary Cell Death Chemistry HEK 293 cells lcsh:R Antibodies Monoclonal Surface Plasmon Resonance Molecular biology ErbB Receptors Molecular Docking Simulation Kinetics HEK293 Cells 030104 developmental biology Monomethyl auristatin E Cell culture Drug Design lcsh:Q Peptides 030217 neurology & neurosurgery Protein Binding Conjugate |
| Zdroj: | Scientific Reports, Vol 9, Iss 1, Pp 1-11 (2019) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-018-37201-6 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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