Translocating Peptides of Biomedical Interest Obtained from the Spike (S) Glycoprotein of the SARS-CoV-2

Abstract

At the beginning of 2020, the pandemic caused by the SARS-CoV-2 virus led to the fast sequencing of its genome to facilitate molecular engineering strategies to control the pathogen’s spread. The spike (S) glycoprotein has been identified as the leading therapeutic agent due to its role in localizing the ACE2 receptor in the host’s pulmonary cell membrane, binding, and eventually infecting the cells. Due to the difficulty of delivering bioactive molecules to the intracellular space, we hypothesized that the S protein could serve as a source of membrane translocating peptides. AHB-1, AHB-2, and AHB-3 peptides were identified and analyzed on a membrane model of DPPC (dipalmitoylphosphatidylcholine) using molecular dynamics (MD) simulations. An umbrella sampling approach was used to quantify the energy barrier necessary to cross the boundary (13.2 to 34.9 kcal/mol), and a flat-bottom pulling helped to gain a deeper understanding of the membrane’s permeation dynamics. Our studies revealed that the novel peptide AHB-1 exhibited comparable penetration potential of already known potent cell-penetrating peptides (CPPs) such as TP2, Buforin II, and Frenatin 2.3s. Results were confirmed by in vitro analysis of the peptides conjugated to chitosan nanoparticles, demonstrating its ability to reach the cytosol and escape endosomes, while maintaining high biocompatibility levels according to standardized assays.

The Adjuvant Activity of BCG Cell Wall Cytoskeleton on a Dengue Virus-2 Subunit Vaccine

“…Consistently, we revealed here that co-delivery of BCG-CWS and a vaccine candidate led to a strong elicitation of CD4 + and CD8 + T cell responses with cytokine production. Because TMC NPs have been proposed to possess an endosomal escape mechanism into cytoplasm, this will further promote the cross-presentation of encapsidated immunogens through the MHC-I pathway [ 34 ]. An increase in activated CD8 + cell expansions seen in mice that received BCG-CWS-adjuvanted vaccine implied that TMC may collaborate with BCG-CWS to augment CTL responses.…”

Rational Discovery of Antimicrobial Peptides by Means of Artificial Intelligence

“…This was achieved by considering several properties to classify membrane-active peptides, including size, Boman Index, net charge at pH 7.4, hydrophobic ratio, hydrophobic moment, aliphatic index, instability index, and isoelectric point. Furthermore, as a negative control, we included AHB-1 (MFVFLVLLPLVS), a potent membrane-translocating peptide that exhibited no antimicrobial activity and was recently discovered by us from a comprehensive analysis of the spike protein of SARS-CoV-2 [ 58 ].…”

Approaches for evaluation of novel CPP-based cargo delivery systems

“…To name a few, Maestro 3D structure modelling software, I-TASSER. For example, new CPPs were derived from the SARS-CoV-2 amino acid sequences using I-TASSER service and characterized with molecular dynamics (MD) simulations (Henao et al, 2022). In case of calculations and simulations it should be kept in mind that these highlight the most probable projections, and should be accompanied by experimental data.…”