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

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

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

Oncolytic Viruses in Combination Therapeutic Approaches with Epigenetic Modulators: Past, Present, and Future Perspectives

According to the World Cancer Report, cancer rates have been increased by 50% with 15 million new cases in the year 2020. Hepatocellular carcinoma (HCC) is the only one of the most common tumors to cause a huge increase in mortality with a survival rate between 40% and 70% at 5 years, due to the high relapse and limitations associated with current therapies. Despite great progress in medicine, oncological research is always looking for new therapies: different technologies have been evaluated in clinical trials and others have been already used in clinics. Among them, oncolytic virotherapy represents a therapeutic option with a widespread possibility of approaches and applications. Oncolytic viruses are naturally occurring, or are engineered, viruses characterized by the unique features of preferentially infecting, replicating, and lysing malignant tumor cells, as well as activating the immune response. The combination of oncolytic virotherapy and chemical drugs are arousing great interest in the tumor treatment. In this scenario, novel and promising anticancer therapies comprise combinations of oncolytic viruses and epigenetic modulators or inhibitors of the signalling pathways. Combination treatments are required to improve the immune response and allow viral entry, replication, and diffusion between proximal cells. In this review, we summarize all combination therapies associated with virotherapy, including co-administered inhibitors of chromatin modifiers (combination strategies) and inserted target sites for miRNAs (recombination or arming strategies)

Antiherpetic Activity of Taurisolo®, a Grape Pomace Polyphenolic Extract

Herpes simplex virus (HSV) is widespread in the population, causing oral or genital ulcers and, rarely, severe complications such as encephalitis, keratitis, and neonatal herpes. Current available anti-HSV drugs are acyclovir and its derivatives, although long-term therapy with these agents can lead to drug resistance. Thus, the discovery of novel antiherpetic compounds merits additional studies. In recent decades, much scientific effort has been invested in the discovery of new synthetic or natural compounds with promising antiviral properties. In our study, we tested the antiviral potential of a novel polyphenol-based nutraceutical formulation (named Taurisolo((R))) consisting of a water polyphenol extract of grape pomace. The evaluation of the antiviral activity was carried out by using HSV-1 and HSV-2 in plaque assay experiments to understand the mechanism of action of the extract. Results were confirmed by real-time PCR, transmission electron microscope (TEM), and fluorescence microscope. Taurisolo((R)) was able to block the viral infection by acting on cells when added together with the virus and also when the virus was pretreated with the extract, demonstrating an inhibitory activity directed to the early phases of HSV-1 and HSV-2 infection. Altogether, these data evidence for the first time the potential use of Taurisolo((R)) as a topical formulation for both preventing and healing herpes lesions.Herpes simplex virus (HSV) is widespread in the population, causing oral or genital ulcers and, rarely, severe complications such as encephalitis, keratitis, and neonatal herpes. Current available anti-HSV drugs are acyclovir and its derivatives, although long-term therapy with these agents can lead to drug resistance. Thus, the discovery of novel antiherpetic compounds merits additional studies. In recent decades, much scientific effort has been invested in the discovery of new synthetic or natural compounds with promising antiviral properties. In our study, we tested the antiviral potential of a novel polyphenol-based nutraceutical formulation (named Taurisolo((R))) consisting of a water polyphenol extract of grape pomace. The evaluation of the antiviral activity was carried out by using HSV-1 and HSV-2 in plaque assay experiments to understand the mechanism of action of the extract. Results were confirmed by real-time PCR, transmission electron microscope (TEM), and fluorescence microscope. Taurisolo((R)) was able to block the viral infection by acting on cells when added together with the virus and also when the virus was pretreated with the extract, demonstrating an inhibitory activity directed to the early phases of HSV-1 and HSV-2 infection. Altogether, these data evidence for the first time the potential use of Taurisolo((R)) as a topical formulation for both preventing and healing herpes lesions

The Broad-Spectrum Antiviral Potential of the Amphibian Peptide AR-23

Viral infections represent a serious threat to the world population and are becoming more frequent. The search and identification of broad-spectrum antiviral molecules is necessary to ensure new therapeutic options, since there is a limited availability of effective antiviral drugs able to eradicate viral infections, and consequently due to the increase of strains that are resistant to the most used drugs. Recently, several studies on antimicrobial peptides identified them as promising antiviral agents. In detail, amphibian skin secretions serve as a rich source of natural antimicrobial peptides. Their antibacterial and antifungal activities have been widely reported, but their exploitation as potential antiviral agents have yet to be fully investigated. In the present study, the antiviral activity of the peptide derived from the secretion of Rana tagoi, named AR-23, was evaluated against both DNA and RNA viruses, with or without envelope. Different assays were performed to identify in which step of the infectious cycle the peptide could act. AR-23 exhibited a greater inhibitory activity in the early stages of infection against both DNA (HSV-1) and RNA (MeV, HPIV-2, HCoV-229E, and SARS-CoV-2) enveloped viruses and, on the contrary, it was inactive against naked viruses (PV-1). Altogether, the results indicated AR-23 as a peptide with potential therapeutic effects against a wide variety of human viruses

Hylin-a1: A Pan-Inhibitor against Emerging and Re-Emerging Respiratory Viruses

Pandemic and epidemic outbreaks of respiratory viruses are a challenge for public health and social care system worldwide, leading to high mortality and morbidity among the human populations. In light of the limited efficacy of current vaccines and antiviral drugs against respiratory viral infections and the emergence and re-emergence of new viruses, novel broad-spectrum antiviral drugs are needed for the prevention and treatment of these infections. Antimicrobial peptides with an antiviral effect, also known as AVPs, have already been reported as potent inhibitors of viral infections by affecting different stages of the virus lifecycle. In the present study, we analyzed the activity of the AVP Hylin-a1, secreted by the frog Hypsiboas albopunctatus, against a wide range of respiratory viruses, including the coronaviruses HCoV-229E and SARS-CoV-2, measles virus, human parainfluenza virus type 3, and influenza virus H1N1. We report a significant inhibitory effect on infectivity in all the enveloped viruses, whereas there was a lack of activity against the naked coxsackievirus B3. Considering the enormous therapeutic potential of Hylin-a1, further experiments are required to elucidate its mechanism of action and to increase its stability by modifying the native sequence

Hydroxylated cyclopamine analogues from Veratrum californicum and their hedgehog pathway inhibiting activity

: Cyclopamine (1), the teratogenic steroidal alkaloid isolated from corn lily (Veratrum californicum), has recently gained renewed interest due to its anticancer potential, that has been translated into the FDA approval of three Hedgehog (Hh) pathway inhibiting antitumor drugs. A chemical analysis of mother liquors obtained from crystallization of cyclopamine, extracted from roots and rhizomes of V. californicum, resulted in the isolation of two unprecedented cyclopamine analogues, 18-hydroxycyclopamine (2) and 24R-hydroxycyclopamine (3), the first compounds of this class to show modifications on rings D-F. The stereostructures of these new natural compounds have been established based on a detailed MS and 1D/2D NMR investigation. The isolated compounds were evaluated with the dual-luciferase bioassay for their inhibition of the hedgehog pathway in comparison to cyclopamine, providing new insights into the structure-activity relationships for this class of compounds

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