Engineering of Janus-Like Dendrimers with Peptides Derived from Glycoproteins of Herpes Simplex Virus Type 1: Toward a Versatile and Novel Antiviral Platform.

Novel antiviral nanotherapeutics, which may inactivate the virus and block it from entering host cells, represent an important challenge to face viral global health emergencies around the world. Using a combination of bioorthogonal copper-catalyzed 1,3-dipolar alkyne/azide cycloaddition (CuAAC) and photoinitiated thiol-ene coupling, monofunctional and bifunctional peptidodendrimer conjugates were obtained. The conjugates are biocompatible and demonstrate no toxicity to cells at biologically relevant concentrations. Furthermore, the orthogonal addition of multiple copies of two different antiviral peptides on the surface of a single dendrimer allowed the resulting bioconjugates to inhibit Herpes simplex virus type 1 at both the early and the late stages of the infection process. The presented work builds on further improving this attractive design to obtain a new class of therapeutics.

Peptides to Overcome the Limitations of Current Anticancer and Antimicrobial Nanotherapies.

Biomedical research devotes a huge effort to the development of efficient non-viral nanovectors (NV) to improve the effectiveness of standard therapies. NVs should be stable, sustainable and biocompatible and enable controlled and targeted delivery of drugs. With the aim to foster the advancements of such devices, this review reports some recent results applicable to treat two types of pathologies, cancer and microbial infections, aiming to provide guidance in the overall design of personalized nanomedicines and highlight the key role played by peptides in this field. Additionally, future challenges and potential perspectives are illustrated, in the hope of accelerating the translational advances of nanomedicine.

Design and Validation of Nanofibers Made of Self-Assembled Peptides to Become Multifunctional Stimuli-Sensitive Nanovectors of Anticancer Drug Doxorubicin.

Self-assembled peptides possess remarkable potential as targeted drug delivery systems and key applications dwell anti-cancer therapy. Peptides can self-assemble into nanostructures of diverse sizes and shapes in response to changing environmental conditions (pH, temperature, ionic strength). Herein, we investigated the development of self-assembled peptide-based nanofibers (NFs) with the inclusion of a cell-penetrating peptide (namely gH625) and a matrix metalloproteinase-9 (MMP-9) responsive sequence, which proved to enhance respectively the penetration and tumor-triggered cleavage to release Doxorubicin in Triple Negative Breast Cancer cells where MMP-9 levels are elevated. The NFs formulation has been optimized via critical micelle concentration measurements, fluorescence, and circular dichroism. The final nanovectors were characterized for morphology (TEM), size (hydrodynamic diameter), and surface charge (zeta potential). The Doxo loading and release kinetics were studied in situ, by optical microspectroscopy (fluorescence and surface-enhanced Raman scattering-SERS). Confocal spectral imaging of the Doxo fluorescence was used to study the TNBC models in vitro, in cells with various MMP-9 levels, the drug delivery to cells as well as the resulting cytotoxicity profiles. The results confirm that these NFs are a promising platform to develop novel nanovectors of Doxo, namely in the framework of TNBC treatment.

Peptides and Dendrimers: How to Combat Viral and Bacterial Infections.

The alarming growth of antimicrobial resistance and recent viral pandemic events have enhanced the need for novel approaches through innovative agents that are mainly able to attach to the external layers of bacteria and viruses, causing permanent damage. Antimicrobial molecules are potent broad-spectrum agents with a high potential as novel therapeutics. In this context, antimicrobial peptides, cell penetrating peptides, and antiviral peptides play a major role, and have been suggested as promising solutions. Furthermore, dendrimers are to be considered as suitable macromolecules for the development of advanced nanosystems that are able to complement the typical properties of dendrimers with those of peptides. This review focuses on the description of nanoplatforms constructed with peptides and dendrimers, and their applications.

Ecotoxicity Evaluation of Pristine and Indolicidin-coated Silver Nanoparticles in Aquatic and Terrestrial Ecosystem.

BACKGROUND: Metallic nanoparticles (NPs) are highly exploited in manufacturing and medical processes in a broad spectrum of industrial applications and in the academic sectors. Several studies have suggested that many metallic nanomaterials including those derived by silver (Ag) are entering the ecosystem to cause significant toxic consequences in cell culture and animal models. However, ecotoxicity studies are still receiving limited attention when designing functionalized and non.-functionalized AgNPs. OBJECTIVE: This study aimed to investigate different ecotoxicological profiles of AgNPs, which were analyzed in two different states: in pristine form uncoated AgNPs and coated AgNPs with the antimicrobial peptide indolicidin. These two types of AgNPs are exploited for a set of different tests using Daphnia magna and Raphidocelis subcapitata, which are representatives of two different levels of the aquatic trophic chain, and seeds of Lepidium sativum, Cucumis sativus and Lactuca sativa. RESULTS: Ecotoxicological studies showed that the most sensitive organism to AgNPs was crustacean D. magna, followed by R. subcapitata and plant seeds, while AgNPs coated with indolicidin (IndAgNPs) showed a dose-dependent decreased toxicity for all three. CONCLUSION: The obtained results demonstrate that high ecotoxicity induced by AgNPs is strongly dependent on the surface chemistry, thus the presence of the antimicrobial peptide. This finding opens new avenues to design and fabricate the next generation of metallic nanoparticles to ensure the biosafety and risk of using engineered nanoparticles in consumer products.

A boost to the antiviral activity: Cholesterol tagged peptides derived from glycoprotein B of Herpes Simplex virus type I.

Conformational changes of viral glycoproteins govern the fusion of viral and cellular membranes in the entry of enveloped viruses. Peptides mimicking domains of viral glycoproteins are apt to interfere with the fusion event, likely hampering the conformational rearrangements from the pre- to the post-fusion structures. We previously developed a peptide sequence with a high potential to inhibit the entry of herpes simplex type 1, which was able to trap glycoprotein B at an intermediate stage, arresting fusion. We propose that similarly to other viruses, membrane targeting through cholesterol conjugation may potently block fusion. The peptide conjugated to polyethylenglycol and cholesterol interacts with viral and cell membranes thanks to the presence of cholesterol and blocks the conformational rearrangements of the glycoprotein B. Here, we also probed the effect of the linker (polyethylenglycol) length on the activity. By targeting the peptide gBh1m to the membranes where fusion occurs and by engineering sequences with increased binding affinity for gB we have enhanced the antiviral potency of our prototype inhibitors. Our results provide proof of concept for the application of cholesterol tagging to develop inhibitors of HSV-1.

A New Hope: Self-Assembling Peptides with Antimicrobial Activity.

Peptide drugs hold great promise for the treatment of infectious diseases thanks to their novel mechanisms of action, low toxicity, high specificity, and ease of synthesis and modification. Naturally developing self-assembly in nature has inspired remarkable interest in self-assembly of peptides to functional nanomaterials. As a matter of fact, their structural, mechanical, and functional advantages, plus their high bio-compatibility and bio-degradability make them excellent candidates for facilitating biomedical applications. This review focuses on the self-assembly of peptides for the fabrication of antibacterial nanomaterials holding great interest for substituting antibiotics, with emphasis on strategies to achieve nano-architectures of self-assembly. The antibacterial activities achieved by these nanomaterials are also described.