Poster De Conférence Année : 2024

Cell-Penetrating Peptides from the SARS-CoV-2 Proteome: Structural Insights and Therapeutic Potential

Résumé

The high infectivity of SARS-CoV-2 makes its proteome a valuable source of new cell-penetrating peptides (CPPs), promising significant discoveries in the coming years. This study aimed to characterize the nanoscale structure of peptides derived from the SARS-CoV-2 spike protein and chimeric sequences combining fragments from SARS-CoV-2 and simian virus 40 (SV-40) proteomes. We investigated the nanoscale organization of peptide/DNA complexes based on selected sequences, studied their effect on the elastic properties of lipid vesicles, and tested their interaction with cells. A chimeric peptide was designed by combining the decameric segment YRLFRKSNLK from the recognition binding domain of the SARS-CoV-2 spike protein with the nuclear localization signal KKKRKV from the SV-40 antigen, with a linker domain WSQP. This sequence was chemically modified to create a lipidated analog by covalently linking a stearoyl tail to the N-terminus of the peptide. Using a range of biophysical approaches, including spectroscopy tools, small-angle X-ray scattering (SAXS), and cryogenic electron microscopy (cryo-EM), we showed that lipidation imparts self-assembling capabilities to the modified chimera, leading to the formation of micelles ~5 nm in size. While the chimera peptide exhibited antimicrobial activity against S. aureus and E. coli strains, with inhibitory concentrations of 27 μM and 55 μM, respectively, the lipidated version was innocuous against bacteria. Interestingly, internalization assays conducted in HeLa cells indicated that the SARS-CoV-2-derived peptides promote the uptake of 200 base pair DNA strands into cells. Importantly, lipidation endowed the sequences with the ability to reach cell nuclei, indicating an advantage for gene therapy. In conclusion, our findings highlight the potential of a new class of CPPs derived from the SARS-CoV-2 proteome and provide insights into their interactions with biomembranes, paving the way for a novel class of peptide-based vehicles for gene delivery applications.

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Dates et versions

hal-04662700 , version 1 (26-07-2024)

Identifiants

  • HAL Id : hal-04662700 , version 1

Citer

Renata Naporano Bicev, Louise E. A. Souza, Ana B. Caliari, Ly Porosk, Ülo Langel, et al.. Cell-Penetrating Peptides from the SARS-CoV-2 Proteome: Structural Insights and Therapeutic Potential. 7th International Conference on Physics and Biological Systems, Jun 2024, Palaiseau, France. ⟨hal-04662700⟩
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