Treatment of microbial‐associated infections continues to be hampered by impaired antibacterial efficiency and the variability in nanomedicines. Herein, an octapeptide library with a double‐layered zipper, constructed via a systematic arrangement, simplifying the sequence and optimizing the structure (diverse motifs including surfactant‐like, central‐bola, and end‐bola), is assessed in terms of biological efficiency and self‐assembly properties. The results indicate that peptides with double‐layered Trp zipper exhibit significant antimicrobial activity. Extracellularly, affinity interactions between micelles and bacteria induce the lateral flow of the membrane and electric potential perturbation. Intracellularly, lead molecules cause apoptosis‐like death, as indicated by excessive accumulation of reactive oxygen species, generation of a DNA ladder, and upregulation of mazEF expression. Among them, RW‐1 performs the best in vivo and in vitro. The intersecting combination of Trp zipper and surfactants possesses overwhelming superiority with respect to bacterial sweepers (therapeutic index [TI] = 52.89), nanostructures (micelles), and bacterial damage compared to RW‐2 (central‐bola) and RW‐3 (end‐bola). These findings confirm that the combination of double‐layered Trp zipper and surfactants has potential for application as a combined motif for combating microbial infection and connects the vast gap between antimicrobial peptides and self‐assembly, such as Jacob's ladder.
Influenza A viral (IAV) fusion peptides are known for their important role in viral-cell fusion process and membrane destabilization potential which are compatible with those of antimicrobial peptides. Thus, by replacing the negatively or neutrally charged residues of FPs with positively charged lysines, we synthesized several potent antimicrobial peptides derived from the fusogenic peptides (FPs) of hemagglutinin glycoproteins (HAs) of IAV. The biological screening identified that in addition to the potent antibacterial activities, these positively charged fusion peptides (pFPs) effectively inhibited the replication of influenza A viruses including oseltamivir-resistant strain. By employing pseudovirus-based entry inhibition assays including H5N1 influenza A virus (IAV), and VSV-G, the mechanism study indicated that the antiviral activity may be associated with the interactions between the HA2 subunit and pFP, of which, the nascent pFP exerted a strong effect to interrupt the conformational changes of HA2, thereby blocking the entry of viruses into host cells. In addition to providing new peptide “entry blockers”, these data also demonstrate a useful strategy in designing potent antibacterial agents, as well as effective viral entry inhibitors. It would be meaningful in treatment of bacterial co-infection during influenza pandemic periods, as well as in our current war against those emerging pathogenic microorganisms such as IAV and HIV.
Cells penetrating molecules in living systems hold promise
of capturing
and eliminating threats and damage that can plan intracellular fate
promptly. However, it remains challenging to construct cell penetration
systems that are physiologically stable with predictable self-assembly
behavior and well-defined mechanisms. In this study, we develop a
core–shell nanoparticle using a hyaluronic acid (HA)-coated
protein transduction domain (PTD) derived from the human immunodeficiency
virus (HIV). This nanoparticle can encapsulate pathogens, transporting
the PTD into macrophages via lipid rafts. PTD forms hydrogen bonds
with the components of the membrane through TAT, which has a high
density of positive charges and reduces the degree of membrane order
through Tryptophan (Trp)-zipper binding to the acyl tails of phospholipid
molecules. HA-encapsulated PTD increases the resistance to trypsin
and proteinase K, thereby penetrating macrophages and eliminating
intracellular infections. Interestingly, the nonagglutination mechanism
of PTD against pathogens ensures the safe operation of the cellular
system. Importantly, PTD can activate the critical pathway of antiferroptosis
in macrophages against pathogen infection. The nanoparticles developed
in this study demonstrate safety and efficacy against Gram-negative
and Gram-positive pathogens in three animal models. Overall, this
work highlights the effectiveness of the PTD nanoparticle in encapsulating
pathogens and provides a paradigm for transduction systems-anti-intracellular
infection therapy.
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