Considerations on the Rational Design of Covalently Conjugated Cell-Penetrating Peptides (CPPs) for Intracellular Delivery of Proteins: A Guide to CPP Selection Using Glucarpidase as the Model Cargo Molecule
| Autor: | Yasaman Behzadipour, Shiva Hemmati |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
cell-penetrating peptides
protein delivery bioconjugation Pharmaceutical Science Conjugated system Article biomacromolecules Analytical Chemistry computational drug design 03 medical and health sciences 0302 clinical medicine Drug Discovery Carboxypeptidase-G2 Humans Physical and Theoretical Chemistry carboxypeptidase G2 030304 developmental biology 0303 health sciences Bioconjugation Base Sequence Chemistry Cell Membrane Organic Chemistry Rational design gamma-Glutamyl Hydrolase Recombinant Proteins Protein Transport Chemistry (miscellaneous) Covalent bond 030220 oncology & carcinogenesis peptide-based drug delivery Biophysics Molecular Medicine Target protein therapeutic peptide-protein Intracellular Conjugate |
| Zdroj: | Molecules Volume 24 Issue 23 |
| ISSN: | 1420-3049 |
| Popis: | Access of proteins to their intracellular targets is limited by a hydrophobic barrier called the cellular membrane. Conjugation with cell-penetrating peptides (CPPs) has been shown to improve protein transduction into the cells. This conjugation can be either covalent or non-covalent, each with its unique pros and cons. The CPP-protein covalent conjugation may result in undesirable structural and functional alterations in the target protein. Therefore, we propose a systematic approach to evaluate different CPPs for covalent conjugations. This guide is presented using the carboxypeptidase G2 (CPG2) enzyme as the target protein. Seventy CPPs &mdash out of 1155&mdash with the highest probability of uptake efficiency were selected. These peptides were then conjugated to the N- or C-terminus of CPG2. Translational efficacy of the conjugates, robustness and thermodynamic properties of the chimera, aggregation possibility, folding rate, backbone flexibility, and aspects of in vivo administration such as protease susceptibility were predicted. The effect of the position of conjugation was evaluated using unpaired t-test (p < 0.05). It was concluded that N-terminal conjugation resulted in higher quality constructs. Seventeen CPP-CPG2/CPG2-CPP constructs were identified as the most promising. Based on this study, the bioinformatics workflow that is presented may be universally applied to any CPP-protein conjugate design. |
| Databáze: | OpenAIRE |
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