Application of Dendrimers for Treating Parasitic Diseases

Despite advances in medical knowledge, parasitic diseases remain a significant global health burden and their pharmacological treatment is often hampered by drug toxicity. Therefore, drug delivery systems may provide useful advantages when used in combination with conventional therapeutic compounds. Dendrimers are three-dimensional polymeric structures, characterized by a central core, branches and terminal functional groups. These nanostructures are known for their defined structure, great water solubility, biocompatibility and high encapsulation ability against a wide range of molecules. Furthermore, the high ratio between terminal groups and molecular volume render them a hopeful vector for drug delivery. These nanostructures offer several advantages compared to conventional drugs for the treatment of parasitic infection. Dendrimers deliver drugs to target sites with reduced dosage, solving side effects that occur with accepted marketed drugs. In recent years, extensive progress has been made towards the use of dendrimers for therapeutic, prophylactic and diagnostic purposes for the management of parasitic infections. The present review highlights the potential of several dendrimers in the management of parasitic diseases

Epigenetic modulator UVI5008 inhibits MRSA by interfering with bacterial gyrase

The impact of multi-drug resistant bacterial strains on human health is reaching worrisome levels. Over 2 million people are infected by resistant bacteria, and more than 700,000 people die each year because of the continuous spread of resistant strains. The development of new antibiotics and the prudent use of existing ones to prolong their lifespan require a constant effort by drug industries and healthcare workers. The re-purposing of existing drugs for use as antimicrobial agents would streamline the development of new antibacterial strategies. As part of this effort, we screened a panel of drugs previously characterized to be epigenetic modulators/pro-apoptotic/differentiative drugs. We selected a few compounds that alter Gram-positive growth. Among these, UVI5008, a derivative of the natural compound psammaplin A (Psa_A), was identified. The interaction of Psa_A with the DNA gyrase enzyme has been shown, and here, we hypothesized and confirmed the gyrase-specific activity by biochemical assays. UVI5008 exhibited growth inhibition activity against Staphylococcus aureus via structural modification of the cell wall, which was observed by SEM electron microscopy. Based on our findings, we propose UVI5008 as an alternative antibacterial compound against methicillin-resistant (Met.R) S. aureus strainsMinisterio de Economía | Ref. SAF2016-77620-R-FEDERXunta de Galicia | Ref. ED431C 29017/61Xunta de Galicia | Ref. ED-431G/02-FEDERProgramma di Ricerca Scientifica di Rilevante Interesse Nazionale | Ref. PRIN-20152TE5PK_00

Antimicrobial Applications of Green Synthesized Bimetallic Nanoparticles from Ocimum basilicum

Antibiotic resistance is an important and emerging alarm for public health that requires development of new potential antibacterial strategies. In recent years, nanoscale materials have emerged as an alternative way to fight pathogens. Many researchers have shown great interest in nanoparticles (NPs) using noble metals, such as silver, gold, and platinum, even though numerous nanomaterials have shown toxicity. To overcome the problem of toxicity, nanotechnology merged with green chemistry to synthesize nature-friendly nanoparticles from plants. Here, we describe the synthesis of NPs using silver (AgNPs) and platinum (PtNPs) alone or in combination (AgPtNPs) in the presence of Ocimum basilicum (O. basilicum) leaf extract. O. basilicum is a well-known medicinal plant with antibacterial compounds. A preliminary chemical–physical characterization of the extract was conducted. The size, shape and elemental analysis were carried out using UV–Visible spectroscopy, dynamic light scattering (DLS), and zeta potential. Transmission electron microscopy (TEM) confirmed polydisperse NPs with spherical shape. The size of the particles was approximately 59 nm, confirmed by DLS analysis, and the polydisperse index was 0.159. Fourier transform infrared (FTIR) demonstrated an effective and selective capping of the phytoconstituents on the NPs. The cytotoxic activities of AgNPs, PtNPs and AgPtNPs were assessed on different epithelial cell models, using the 3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyltetrazolium bromide (MTT) cell proliferation assay, and discovered low toxicity, with a cell viability of 80%. The antibacterial potential of the NPs was evaluated against Escherichia coli (E. coli), Enterococcus faecalis (E. faecalis), Klebsiella pneumonia (K. pneumoniae), and Staphylococcus aureus (S. aureus) strains. Minimum inhibitory concentration (MIC) assays showed AgPtNP activity till the least concentration of NPs (3.15–1.56 g/mL) against ATCC, MS, and MDR E. coli, E. faecalis, and S. aureus and the Kirby–Bauer method showed that AgPtNPs gave a zone of inhibition for Gram-positive and Gram-negative bacteria in a range of 9–25 mm. In addition, we obtained AgPtNP synergistic activity in combination with vancomycin or ampicillin antibiotics. Taken together, these results indicate that bimetallic nanoparticles, synthesized from O. basilicum leaf extract, could represent a natural, ecofriendly, cheap, and safe method to produce alternative antibacterial strategies with low cytotoxicity

Ophthalmic Solutions with a Broad Antiviral Action: Evaluation of Their Potential against Ocular Herpetic Infections

HSV-1 can be associated with severe and recurrent eye infections characterized by a strong inflammatory response that leads to blepharoconjunctivitis, epithelial and stromal keratitis, and retinal necrosis. The incidence of HSV-1 keratitis is 1.5 million every year worldwide, including more than 40,000 new cases exhibiting serious visual failures. Generally, the therapy uses antiviral drugs to promote healing; however, there are currently no compounds that are able to completely eradicate the virus. In addition, the phenomenon of resistance is rapidly spreading among HSV-1 strains, creating mutants developing resistance to the common antiviral drugs; therefore, deep research on this issue is warranted. The efficacy of different ophthalmic solutions already on the market was evaluated for reducing HSV-1 infection. Different plaque assays were set up on epithelial cells, revealing that two ophthalmic solutions were able to inhibit viral replication in the early stages of infection. The data were further confirmed by molecular tests analyzing the expression levels of the principal genes involved in HSV-1 infection, and a strong reduction was observed after only 1 min of eye-drop treatment. Collectively, these results suggested the use of ophthalmic solutions as potential antiviral options for the treatment of ocular herpetic infection

Synthesis of Chitosan-Coated Silver Nanoparticle Bioconjugates and Their Antimicrobial Activity against Multidrug-Resistant Bacteria

The increase in multidrug-resistant bacteria represents a true challenge in the pharmaceutical and biomedical fields. For this reason, research on the development of new potential antibacterial strategies is essential. Here, we describe the development of a green system for the synthesis of silver nanoparticles (AgNPs) bioconjugated with chitosan. We optimized a Prunus cerasus leaf extract as a source of silver and its conversion to chitosan–silver bioconjugates (CH-AgNPs). The AgNPs and CH-AgNPs were characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FT-IR), ultraviolet–visible spectroscopy (UV–Vis), and zeta potential measurement (Z-potential). The cytotoxic activity of AgNPs and CH-AgNPs was assessed on Vero cells using the 3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyltetrazolium bromide (MTT) cell proliferation assay. The antibacterial activity of AgNPs and CH-AgNPs synthesized using the green system was determined using the broth microdilution method. We evaluated the antimicrobial activity against standard ATCC and clinically isolated multisensitive (MS) and multidrug-resistant bacteria (MDR) Escherichia coli (E. coli), Enterococcus faecalis (E. faecalis), Klebsiella pneumonia (K. pneumoniae), and Staphylococcus aureus (S. aureus), using minimum inhibitory concentration (MIC) assays and the broth dilution method. The results of the antibacterial studies demonstrate that the silver chitosan bioconjugates were able to inhibit the growth of MDR strains more effectively than silver nanoparticles alone, with reduced cellular toxicity. These nanoparticles were stable in solution and had wide-spectrum antibacterial activity. The synthesis of silver and silver chitosan bioconjugates from Prunus cerasus leaf extracts may therefore serve as a simple, ecofriendly, noncytotoxic, economical, reliable, and safe method to produce antimicrobial compounds with low cytotoxicity

Spike-mediated viral membrane fusion is inhibited by a specific anti-IFITM2 monoclonal antibody

The early steps of viral infection involve protein complexes and structural lipid rearrangements which characterize the peculiar strategies of each virus to invade permissive host cells. Members of the human immune-related interferon-induced transmembrane (IFITM) protein family have been described as inhibitors of the entry of a broad range of viruses into the host cells. Recently, it has been shown that SARS-CoV-2 is able to hijack IFITM2 for efficient infection. Here, we report the characterization of a newly generated specific anti-IFITM2 mAb able to impair Spike-mediated internalization of SARS-CoV-2 in host cells and, consequently, to reduce the SARS-CoV-2 cytopathic effects and syncytia formation. Furthermore, the anti-IFITM2 mAb reduced HSVs- and RSV-dependent cytopathic effects, suggesting that the IFITM2-mediated mechanism of host cell invasion might be shared with other viruses besides SARS-CoV-2. These results show the specific role of IFITM2 in mediating viral entry into the host cell and its candidacy as a cell target for antiviral therapeutic strategies

Antiviral Activity of Vitis vinifera Leaf Extract against SARS-CoV-2 and HSV-1

Vitis vinifera represents an important and renowned source of compounds with significant biological activity. Wines and winery bioproducts, such as grape pomace, skins, and seeds, are rich in bioactive compounds against a wide range of human pathogens, including bacteria, fungi, and viruses. However, little is known about the biological properties of vine leaves. The aim of this study was the evaluation of phenolic composition and antiviral activity of Vitis vinifera leaf extract against two human viruses: the Herpes simplex virus type 1 (HSV-1) and the pandemic and currently widespread severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). About 40 phenolic compounds were identified in the extract by HPLC-MS/MS analysis: most of them were quercetin derivatives, others included derivatives of luteolin, kaempferol, apigenin, isorhamnetin, myricetin, chrysoeriol, biochanin, isookanin, and scutellarein. Leaf extract was able to inhibit both HSV-1 and SARS-CoV-2 replication in the early stages of infection by directly blocking the proteins enriched on the viral surface, at a very low concentration of 10 μg/mL. These results are very promising and highlight how natural extracts could be used in the design of antiviral drugs and the development of future vaccines

Effective Neutralizing Antibody Response Against SARS-CoV-2 Virus and Its Omicron BA.1 Variant in Fully Vaccinated Hematological Patients

SARS-CoV-2 and its variants cause CoronaVIrus Disease 19 (COVID-19), a pandemic disease. Hematological malignancies increase susceptibility to severe COVID-19 due to immunosuppression. Anti-SARS-CoV-2 neutralizing antibodies protect against severe COVID-19. This retrospective real-life study aimed to evaluate seropositivity and neutralizing antibody rates against SARS-CoV-2 and its Omicron BA.1 variant in hematological patients. A total of 106 patients with different hematologic malignancies, who have mostly received three or more vaccine doses (73%), were included in this study. Serum was collected between May and June 2022. The primary endpoint was anti-SARS-CoV-2 antibody response against ancestral (wild type; wt) and Omicron BA.1 virus, defined as a neutralizing antibody titer ≥ 1:10. Adequate neutralizing antibody response was observed in 75 (71%) and 87 (82%) of patients for wt and Omicron BA.1 variants, respectively.However, patients with B-cell lymphoproliferative disorders and/or those treated with anti-CD20 monoclonal antibodies in the prior 12 months showed a lower seropositivity rate compared to other patients against both Omicron BA.1 variant (73% vs 91%; P = 0.02) and wt virus (64% vs 78%; P = 0.16). Our real-life experience confirmed that full vaccination against SARS-CoV-2 induces adequate neutralizing antibody protection for both the wt virus and Omicron BA.1 variants, even in hematological frail patients. However, protective measures should be maintained in hematological patients, especially those with B-cell lymphoproliferative diseases treated with anti-CD20 monoclonal antibodies, because these subjects could have a reduced neutralizing antibody production

Regulation of m6A Methylation as a New Therapeutic Option against COVID-19

The rapid spread of SARS-CoV-2 and the resulting pandemic has led to a spasmodic search for approaches able to limit the diffusion of the disease. The epigenetic machinery has aroused considerable interest in the last decades, and much evidence has demonstrated that this type of modification could regulate the early stages of viral infection. Recently it was reported that N6-methyladenosine (m6A) influences SARS-CoV-2 replication, although its role remains to be further investigated. The knockdown of enzymes involved in the m6A pathway could represent an optimal strategy to deepen the epigenetic mechanism. In the present study, we blocked the catalytic activity of the fat mass and obesity-associated protein (FTO) by using the selective inhibitor rhein. We observed a strong broad-spectrum reduction of infectivity caused by various coronaviruses, including SARS-CoV-2. This effect could be due to the modulation of m6A levels and could allow identification of this modification as a new therapeutic target to treat SARS-CoV-2 infection

HOST DEFENSE TEMPORIN 1 PEPTIDES AND THEIR POTENTIAL AS ANTIVIRAL AGENTS

HOST DEFENSE TEMPORIN 1 PEPTIDES AND THEIR POTENTIAL AS ANTIVIRAL AGENTS antimicrobial activity on a large number of invading microorganisms. They represent the most ancient and fast-acting elements of the host’s innate defence system against microbial pathogens. Methods: In this scenario, AMPs have emerged as good candidates for the generation of new anti-infective agents. While the antibacterial activity has been deeply investigated, the notions available for antiviral activities are still underexplored. Furthermore, due to their chemical and biological instability only few AMPs are currently in clinical trials as antimicrobial agents. The amphibian temporins represent one of the largest families (more than 100 members) and are among the smallest-sized AMPs (10-16 amino acids) found in nature to date. Temporins are known to be active particularly against Gram-positive bacteria, with minimal inhibitory concentrations ranging from 2.5 μM to 20 μM. In details, we focused on Temporin 1 (TL1) analogues. Results: Those peptides have been modified in order to increase the peptide stability and antimicrobial activity. We then performed a structure-activity relationship study of these peptides with the aim to improve their antimicrobial efficacy without altering their nonhemolytic character. Conclusion: Among the peptides generated, several of them have shown higher in solution stability, low toxicity and a significant decrease of Herpes Simplex virus type 1 infectivity. Our results show novel possible applications of Temporin 1 peptides in the field of antivirals