Designed filamentous cell penetrating peptides: probing supramolecular structure-dependent membrane activity and transfection efficiency

Xu, Dawei; Dustin, Derek; Jiang, Linhai; Samways, Damien S. K.; Dong, He

doi:10.1039/c5cc02699g

Cited by 30 publications

(34 citation statements)

References 35 publications

(10 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This ability to assume a higher order of organization through folding (intramolecular weak interactions) can also be achieved via controlled self-assembly through intermolecular, non-covalent interactions between CPP monomeric units [ 36 ]. While folding is widely explored in the CPP field, little attention has been paid to the propensity of CPPs to self-assemble in a controlled fashion.…”

Section: From Protein Domains To the Design Of Peptides With Cell mentioning

confidence: 99%

“…This field has experienced rapid growth, and peptide self-assembly is now increasingly studied for a wide range of applications in biomedicine, including drug-delivery, diagnostics, tissue engineering, and regenerative medicine [ 109 , 110 , 115 , 151 , 155 , 156 ]. Although peptide self-assembly has been exploited for several applications, only recently has this concept been introduced into the field of CPPs [ 36 , 157 ].…”

Section: Design Strategiesmentioning

confidence: 99%

“…Dong and coworkers introduced the concept of filamentous CPPs (FCPPs) based on cationic multi-domain peptides, providing examples of supramolecular structure-dependent membrane activity [ 36 , 159 ]. The supramolecular approach to obtain FCPPs (based on β-sheet structures) was reported for cationic peptides with generic structure K x (QL) y K xz or K x (QW) y K xz .…”

Section: Design Strategiesmentioning

confidence: 99%

“…DNA delivery with this peptide was 200- and 400-fold higher in the HEK293 and HeLa cell lines, respectively. In this example, the fibrilllar shape of the supramolecular nanostructure with the precise balance of charge distribution and conformational flexibility, was responsible for higher uptake [ 36 ]. This system was also used to deliver impermeable anticancer drugs.…”

Section: Design Strategiesmentioning

confidence: 99%

See 3 more Smart Citations

Cell-Penetrating Peptides: Design Strategies beyond Primary Structure and Amphipathicity

2017

View full text Add to dashboard Cite

Efficient intracellular drug delivery and target specificity are often hampered by the presence of biological barriers. Thus, compounds that efficiently cross cell membranes are the key to improving the therapeutic value and on-target specificity of non-permeable drugs. The discovery of cell-penetrating peptides (CPPs) and the early design approaches through mimicking the natural penetration domains used by viruses have led to greater efficiency of intracellular delivery. Following these nature-inspired examples, a number of rationally designed CPPs has been developed. In this review, a variety of CPP designs will be described, including linear and flexible, positively charged and often amphipathic CPPs, and more rigid versions comprising cyclic, stapled, or dimeric and/or multivalent, self-assembled peptides or peptido-mimetics. The application of distinct design strategies to known physico-chemical properties of CPPs offers the opportunity to improve their penetration efficiency and/or internalization kinetics. This led to increased design complexity of new CPPs that does not always result in greater CPP activity. Therefore, the transition of CPPs to a clinical setting remains a challenge also due to the concomitant involvement of various internalization routes and heterogeneity of cells used in the in vitro studies.

show abstract

Section: From Protein Domains To the Design Of Peptides With Cell mentioning

confidence: 99%

Section: Design Strategiesmentioning

confidence: 99%

Section: Design Strategiesmentioning

confidence: 99%

Section: Design Strategiesmentioning

confidence: 99%

See 2 more Smart Citations

Cell-Penetrating Peptides: Design Strategies beyond Primary Structure and Amphipathicity

2017

View full text Add to dashboard Cite

show abstract

“…Notably, supramolecular peptides may also overcome some of the intrinsic limitations associated with single chain peptides, e.g. stability to greatly expand their biomedical utility [31] , [32] , [33] , [34] .…”

Section: Introductionmentioning

confidence: 99%

Fabrication of self-assembling nanofibers with optimal cell uptake and therapeutic delivery efficacy

Samways

Dong

2017

Bioactive Materials

Self Cite

View full text Add to dashboard Cite

Effective strategies to fabricate finite organic nanoparticles and understanding their structure-dependent cell interaction is highly important for the development of long circulating nanocarriers in cancer therapy. In this contribution, we will capitalize on our recent development of finite supramolecular nanofibers based on the self-assembly of modularly designed cationic multidomain peptides (MDPs) and use them as a model system to investigate structure-dependent cell penetrating activity. MDPs self-assembled into nanofibers with high density of cationic charges at the fiber-solvent interface to interact with the cell membrane. However, despite the multivalent charge presentation, not all fibers led to high levels of membrane activity and cellular uptake. The flexibility of the cationic charge domains on self-assembled nanofibers plays a key role in effective membrane perturbation. Nanofibers were found to sacrifice their dimension, thermodynamic and kinetic stability for a more flexible charge domain in order to achieve effective membrane interaction. The increased membrane activity led to improved cell uptake of membrane-impermeable chemotherapeutics through membrane pore formation. In vitro cytotoxicity study showed co-administering of water-soluble doxorubicin with membrane-active peptide nanofibers dramatically reduced the IC50 by eight folds compared to drug alone. Through these detailed structure and activity studies, the acquired knowledge will provide important guidelines for the design of a variety of supramolecular cell penetrating nanomaterials not limited to peptide assembly which can be used to probe various complex biological processes.

show abstract

Self‐assembling Peptides with Internal Ionizable Unnatural Amino Acids: A General Approach to pH‐responsive Peptide Materials

Asokan-Sheeja

Yang

Adones

et al. 2022

Chemistry An Asian Journal

Self Cite

View full text Add to dashboard Cite

Self‐assembled peptides are an emerging family of biomaterials that show great promise for a range of biomedical and biotechnological applications. Introducing and tuning the pH‐responsiveness of the assembly is highly desirable for improving their biological activities. Inspired by proteins with internal ionizable residues, we report a simple but effective approach to constructing pH‐responsive peptide assembly containing unnatural ionic amino acids with an aliphatic tertiary amine side chain. Through a combined experimental and computational investigation, we demonstrate that these residues can be accommodated and stabilized within the internal hydrophobic compartment of the peptide assembly. The hydrophobic microenvironment shifts their pKa significantly from a basic pH typically found for free amines to a more biologically relevant pH in the weakly acidic range. The pH‐induced ionization and ionization‐dependent self‐assembly and disassembly are thoroughly investigated and correlated with the biological activity of the assembly. This new approach has unique advantages in tuning the pH‐responsiveness of self‐assembled peptides across a large pH range in a complex biological environment. We anticipate the ionizable amino acids developed here can be widely applicable to the synthesis and self‐assembly of many amphiphilic peptides with endowed pH‐responsive properties to enhance their biological activities toward applications ranging from targeted therapeutic delivery to proton transport.

show abstract

Designed filamentous cell penetrating peptides: probing supramolecular structure-dependent membrane activity and transfection efficiency

Abstract: In this work, we will demonstrate a simple yet powerful strategy to assemble single-chain cationic peptides into macromolecular filamentous nanostructures with dramatically improved membrane activity, stability and transfection efficiency.

Cited by 30 publications

References 35 publications

Cell-Penetrating Peptides: Design Strategies beyond Primary Structure and Amphipathicity

Cell-Penetrating Peptides: Design Strategies beyond Primary Structure and Amphipathicity

Fabrication of self-assembling nanofibers with optimal cell uptake and therapeutic delivery efficacy

Self‐assembling Peptides with Internal Ionizable Unnatural Amino Acids: A General Approach to pH‐responsive Peptide Materials

Contact Info

Product

Resources

About