| Full text | |
| Author(s): |
de Mello, Lucas R.
[1]
;
Porosk, Ly
[2]
;
Lourenco, Thiago C.
[1]
;
Garcia, Bianca B. M.
[1]
;
Costa, Carlos A. R.
[3]
;
Han, Sang W.
[1]
;
de Souza, Juliana S.
[4]
;
Langel, Ulo
[2, 5]
;
da Silva, Emerson R.
[1]
Total Authors: 9
|
| Affiliation: | [1] Univ Fed Sao Paulo, Dept Biofts, BR-04023062 Sao Paulo - Brazil
[2] Univ Tartu, Inst Technol, EE-50411 Tartu - Estonia
[3] Ctr Nacl Pesquisa Energia & Mat CNPEM, Lab Nacl Nanotecnol LNNano, BR-13083861 Campinas - Brazil
[4] Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210580 Santo Andre, SP - Brazil
[5] Stockholm Univ, Dept Biochem & Biophys, SE-10691 Stockholm - Sweden
Total Affiliations: 5
|
| Document type: | Journal article |
| Source: | ACS APPLIED BIO MATERIALS; v. 4, n. 8, p. 6404-6416, AUG 16 2021. |
| Web of Science Citations: | 1 |
| Abstract | |
Cell-penetrating peptides (CPPs) are a topical subject potentially exploitable for creating nanotherapeutics for the delivery of bioactive loads. These compounds are often classified into three major categories according to their physicochemical characteristics: cationic, amphiphilic, and hydrophobic. Among them, the group of hydrophobic CPPs has received increasing attention in recent years due to toxicity concerns posed by highly cationic CPPs. The hexapeptide PFVYLI (P, proline; F, phenylalanine; V, valine; Y, tyrosine; L, leucine; and I, isoleucine), a fragment derived from the C-terminal portion of alpha 1-antitrypsin, is a prototypal example of hydrophobic CPP. This sequence shows reduced cytotoxicity and a capacity of nuclear localization, and its small size readily hints at its suitability as a building block to construct nanostructured materials. In this study, we examine the self-assembling properties of PFVYLI and investigate its ability to form noncovalent complexes with nucleic acids. By using a combination of biophysical tools including synchrotron small-angle X-ray scattering and atomic force microscopy-based infrared spectroscopy, we discovered that this CPP self-assembles into discrete nanofibrils with remarkable amyloidogenic features. Over the course of days, these fibrils coalesce into rodlike crystals that easily reach the micrometer range. Despite lacking cationic residues in the composition, PFVYLI forms noncovalent complexes with nucleic acids that retain beta-sheet pairing found in amyloid aggregates. In vitro vectorization experiments performed with doublestranded DNA fragments indicate that complexes promote the internalization of nucleic acids, revealing that tropism toward cell membranes is preserved upon complexation. On the other hand, transfection assays with splice-correction oligonucleotides (SCOs) for luciferase expression show limited bioactivity across a narrow concentration window, suggesting that the propensity to form amyloidogenic aggregates may trigger endosomal entrapment. We anticipate that the findings presented here open perspectives for using this archetypical hydrophobic CPP in the fabrication of nanostructured scaffolds, which potentially integrate properties of amyloids and translocation capabilities of CPPs. (AU) | |
| FAPESP's process: | 19/20907-7 - Structural organization and bioactivity in peptide and nucleotide self-assemblies |
| Grantee: | Emerson Rodrigo da Silva |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 19/19719-1 - Bioactive peptide matrices: from molecular structure to biomedical applications |
| Grantee: | Lucas Rodrigues de Mello |
| Support Opportunities: | Scholarships in Brazil - Doctorate |