![]() For optimization of SNCP, we also address how the internal environment of porous nanoparticles affects secondary structures of peptides in detail. In addition, in situ peptide stapling is employed sequentially via click reaction to ensure irreversible and thermally stable α-helical structure of the peptide without aggregation. We reveal that a model peptide is successfully transformed from a random-coil structure to an α-helical structure inside pores of SNCP. Here, we demonstrate a smart integrated system, designated as synthetic nano-chaperone for peptide (SNCP) as a nanoreactor for engineering chemically stapled α-helical peptide with high stability as well as a delivery carrier for eliciting efficient tumor control via direct intracellular delivery of the therapeutic anti-cancer peptide in its bioactive conformation (Fig. ![]() Therefore, porous nanoparticles are regarded as one of the most promising delivery vehicles for biomedical applications and these previous studies have inspired us to develop a synthetic chaperone system based on porous nanoparticles suitable for assisting proper folding of therapeutic α-helical peptides and for intracellular peptide delivery vehicle at the same time. Among them, porous nanoparticles have shown great potential in delivering bio-macromolecules such as plasmid DNA 24, siRNA 25, 26, 27 and proteins 28 to target cells due to tunable pore size, large surface area, and flexible surface modification 29, 30. In this regard, nanomaterials harnessing various components such as cyclodextrins 14, polymers 15, 16, metallic nanoparticles 17, 18, silica 19, 20 and self-assembled nanostructures 21, 22, 23 have been developed as artificial molecular chaperones. Nevertheless, pragmatic challenges still remain for practical biological and medical applications of α-helical peptides due to insufficient cellular uptake and instability in vivo 6. To overcome these drawbacks, various strategies have been suggested including peptide stapling methods that fix α-helical structure of peptides through covalent bond formation 6, 7, 8, 9, 10, 11, 12, 13. However, they have intrinsic weakness, including poor conformational stability and short half-life by proteolytic degradation and fast clearance 5. ![]() Therapeutic α-helical peptides have gradually emerged as attractive drug candidates for treatment of cancer and diseases. To solve these problems, artificial biological systems emulating molecular chaperones have attracted lots of attention in the field of biotechnology and biomedicine. In many cases, proteins and peptides manufactured from Escherichia coli or chemical synthesis do not show enough biological activities in biomedical applications mostly due to undesirable aggregation, poor solubility, or inactive conformation 4. With hydrophobic segments or an internal space, the chaperones not only trap unfolded initial proteins or intermediates but also prevent an irreversible aggregation of proteins during the refolding process 1, 2, 3. Molecular chaperones play important roles in a living system to control protein folding/unfolding and guide it to native structure from partially folded states. These data indicate that the bio-inspired SNCP system combining nanoreactor and delivery carrier could provide a strategy to expedite the development of peptide therapeutics by overcoming existing drawbacks of α-helical peptides as drug candidates. SNCP improves cellular uptake and bioavailability of the anti-cancer peptide, so the cancer growth is effectively inhibited in vivo. Then, SNCP subsequently delivers the stabilized therapeutic α-helical peptides into cancer cells, resulting in high therapeutic efficacy. In addition, SNCP with optimized inner surface modification not only improves thermal stability for α-helical peptide but also supports the peptide stapling methods in situ, serving as a nanoreactor. The Synthetic Nano- Chaperone for Peptide (SNCP) based on porous nanoparticles provides an internal hydrophobic environment which contributes in stabilizing secondary structure of encapsulated α-helical peptides due to the hydrophobic internal environments. Here, we report bio-inspired multifunctional porous nanoparticles to modulate proper folding and intracellular delivery of therapeutic α-helical peptide. Artificial, synthetic chaperones have attracted much attention in biomedical research due to their ability to control the folding of proteins and peptides.
0 Comments
Leave a Reply. |