The herpes simplex virus (HSV) is a double-stranded DNA human virus that causes persistent infections with recurrent outbreaks. HSV exists in two forms: HSV-1, responsible for oral herpes, and HSV-2, primarily causing genital herpes. Both types can lead to significant complications, including neurological issues. Conventional treatment, involving acyclovir and its derivatives, faces challenges due to drug resistance. This underscores the imperative for continual research and development of new drugs, with a particular emphasis on exploring the potential of natural antivirals. Flavonoids have demonstrated promise in combating various viruses, including those within the herpesvirus family. This review, delving into recent studies, reveals the intricate mechanisms by which flavonoids decode their antiviral capabilities against HSV. By disrupting key stages of the viral life cycle, such as attachment to host cells, entry, DNA replication, latency, and reactivation, flavonoids emerge as formidable contenders in the ongoing battle against HSV infections.

• Keywords
• HSV life cycle, HSV-1, HSV-2, antiviral properties, cellular pathways, drug resistance, flavonoids, herpes simplex virus, host–virus interaction, natural antivirals, natural products,
• MeSH
• Antiviral Agents pharmacology   therapeutic use   MeSH
• Flavonoids pharmacology   therapeutic use   MeSH
• Herpes Simplex * drug therapy   MeSH
• Humans MeSH
• Herpesvirus 1, Human * physiology   MeSH
• Life Cycle Stages MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antiviral Agents MeSH
• Flavonoids MeSH

Human herpesviruses (HHVs) are large DNA viruses with highly infectious characteristics. HHVs can induce lytic and latent infections in their host, and most of these viruses are neurotropic, with the capacity to generate severe and chronic neurological diseases of the peripheral nervous system (PNS) and central nervous system (CNS). Treatment of HHV infections based on strategies that include natural products-derived drugs is one of the most rapidly developing fields of modern medicine. Therefore, in this paper, we lend insights into the recent advances that have been achieved during the past five years in utilizing flavonoids as promising natural drugs for the treatment of HHVs infections of the nervous system such as alpha-herpesviruses (herpes simplex virus type 1, type 2, and varicella-zoster virus), beta-herpesviruses (human cytomegalovirus), and gamma-herpesviruses (Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus). The neurological complications associated with infections induced by the reviewed herpesviruses are emphasized. Additionally, this work covers all possible mechanisms and pathways by which flavonoids induce promising therapeutic actions against the above-mentioned herpesviruses.

• Keywords
• Epstein–Barr virus, HSV-1, HSV-2, Kaposi sarcoma-associated herpesvirus, flavonoids, herpes simplex virus, human cytomegalovirus, mechanisms of action, nervous system, neurological diseases, varicella-zoster virus,
• MeSH
• Central Nervous System MeSH
• Flavonoids pharmacology   therapeutic use   MeSH
• Herpesviridae Infections * drug therapy   MeSH
• Epstein-Barr Virus Infections * MeSH
• Humans MeSH
• Herpesvirus 1, Human * genetics   MeSH
• Herpesvirus 4, Human genetics   MeSH
• Herpesvirus 3, Human genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Flavonoids MeSH

A series of new heteroleptic copper(II) complexes of the composition [Cu(L)(bpy)]NO3·2MeOH (1), [Cu(L)(dimebpy)]NO3·2H2O (2), [Cu(L)(phen)]NO3·2MeOH (3), [Cu(L)(bphen)]NO3·MeOH (4), [Cu(L)(dppz)]NO3·MeOH (5) was prepared, where HL = 3-(3,4-dihydroxyphenyl)-5-hydroxy-8,8-dimethyl-6-(3-methylbut-2-ene-1-yl)-4H,8H-benzo[1,2-b:3,4-b']dipyran-4-one, (pomiferin) and bpy = 2,2'-bipyridine, dimebpy = 4,4'-dimethyl-2,2'-bipyridine, phen = 1,10-phenanthroline, bphen = 4,7-diphenyl-1,10-phenanthroline, and dppz = dipyrido[3,2-a:2',3'-c]phenazine. The complexes were characterized using elemental analysis, infrared and UV/Vis spectroscopies, mass spectrometry, thermal analysis and conductivity measurements. The in vitro cytotoxicity, screened against eight human cancer cell lines (breast adenocarcinoma (MCF-7), osteosarcoma (HOS), lung adenocarcinoma (A549), prostate adenocarcinoma (PC-3), ovarian carcinoma (A2780), cisplatin-resistant ovarian carcinoma (A2780R), colorectal adenocarcinoma (Caco-2) and monocytic leukemia (THP-1), revealed the complexes as effective antiproliferative agents, with the IC50 values of 2.2-13.0 μM for the best performing complexes 3 and 5. All the complexes 1-5 showed the best activity against the A2780R cells (IC50 = 2.2-6.6 μM), and moreover, the complexes demonstrated relatively low toxicity on healthy human hepatocytes, with IC50 > 100 μM. The complexes were evaluated by the Annexin V/propidium iodide apoptosis assay, induction of cell cycle modifications in A2780 cells, production of reactive oxygen species (ROS), perturbation of mitochondrial membrane potential, inhibition of apoptosis and inflammation-related signaling pathways (NF-κB/AP-1 activity, NF-κB translocation, TNF-α secretion), and tested for nuclease mimicking activity. The obtained results revealed the corresponding complexes to be effective antiproliferative and anti-inflammatory agents.

• Keywords
• ROS, cell cycle, copper(II) complexes, in vitro cytotoxicity, inflammation, nuclease activity, pomiferin,
• MeSH
• Anti-Inflammatory Agents pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Benzopyrans chemistry   pharmacology   MeSH
• Flavonoids metabolism   pharmacology   MeSH
• Isoflavones chemistry   pharmacology   MeSH
• Coordination Complexes chemistry   pharmacology   MeSH
• Humans MeSH
• Copper chemistry   metabolism   pharmacology   MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Inflammatory Agents MeSH
• Benzopyrans MeSH
• Flavonoids MeSH
• Isoflavones MeSH
• Coordination Complexes MeSH
• Copper MeSH
• pomiferin MeSH Browser
• Antineoplastic Agents MeSH
• Reactive Oxygen Species MeSH

Human herpesviruses are known to induce a broad spectrum of diseases, ranging from common cold sores to cancer, and infections with some types of these viruses, known as human oncogenic herpesviruses (HOHVs), can cause cancer. Challenges with viral latency, recurrent infections, and drug resistance have generated the need for finding new drugs with the ability to overcome these barriers. Berberine (BBR), a naturally occurring alkaloid, is known for its multiple biological activities, including antiviral and anticancer effects. This paper comprehensively compiles all studies that have featured anti-HOHV properties of BBR along with promising preventive effects against the associated cancers. The mechanisms and pathways induced by BBR via targeting the herpesvirus life cycle and the pathogenesis of the linked malignancies are reviewed. Approaches to enhance the therapeutic efficacy of BBR and its use in clinical practice as an anti-herpesvirus drug are also discussed.

• Keywords
• Epstein–Barr virus, Kaposi’s sarcoma-associated herpesvirus, berberine, cancer, herpes simplex virus, human cytomegalovirus, inflammation, oncogenic herpesviruses,
• MeSH
• Antiviral Agents therapeutic use   MeSH
• Berberine therapeutic use   MeSH
• Herpesviridae classification   drug effects   pathogenicity   MeSH
• Herpesviridae Infections complications   drug therapy   MeSH
• Carcinogenesis drug effects   MeSH
• Clinical Trials as Topic MeSH
• Virus Latency drug effects   MeSH
• Humans MeSH
• Mice MeSH
• Neoplasms drug therapy   virology   MeSH
• Virus Replication drug effects   MeSH
• Inflammation drug therapy   virology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antiviral Agents MeSH
• Berberine MeSH

Herpesviruses are DNA viruses that infect humans and animals with the ability to induce latent and lytic infections in their hosts, causing critical health complications. The enrolment of nutraceutical anti-herpesvirus drugs in clinical investigations with promising levels of reduced resistance, free or minimal cellular toxicity, and diverse mechanisms of action might be an effective way to defeat challenges that hurdle the progress of anti-herpesvirus drug development, including the problems with drug resistance and recurrent infections. Therefore, in this review, we aim to hunt down all investigations that feature the curative properties of curcumin, a principal bioactive phenolic compound of the spice turmeric, in regard to various human and animal herpesvirus infections and inflammation connected with these diseases. Curcumin was explored with potent antiherpetic actions against herpes simplex virus type 1 and type 2, human cytomegalovirus, Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus, bovine herpesvirus 1, and pseudorabies virus. The mechanisms and pathways by which curcumin inhibits anti-herpesvirus activities by targeting multiple steps in herpesvirus life/infectious cycle are emphasized. Improved strategies to overcome bioavailability challenges that limit its use in clinical practice, along with approaches and new directions to enhance the anti-herpesvirus efficacy of this compound, are also reviewed. According to the reviewed studies, this paper presents curcumin as a promising natural drug for the prevention and treatment of herpesvirus infections and their associated inflammatory diseases.

• Keywords
• Curcuma longa L., curcumin, herpesviruses, inflammation, mechanisms and pathways, phenolics, viral infections,
• Publication type
• Journal Article MeSH
• Review MeSH

While few studies have revealed the biological properties of brassicasterol, a phytosterol, against some biological and molecular targets, it is believed that there are still many activities yet to be studied. In this work, brassicasterol exerts a therapeutic utility in an in vitro setting against herpes simplex virus type 1 (HSV-1) and Mycobacterium tuberculosis (Mtb) as well as a considerable inhibitory property against human angiotensin-converting enzyme (ACE) that plays a dynamic role in regulating blood pressure. The antireplicative effect of brassicasterol against HSV-1 is remarkably detected (50% inhibitory concentration (IC50): 1.2 µM; selectivity index (SI): 41.7), while the potency of its effect is ameliorated through the combination with standard acyclovir with proper SI (IC50: 0.7 µM; SI: 71.4). Moreover, the capacity of this compound to induce an adequate level of antituberculosis activity against all Mtb strains examined (minimum inhibitory concentration values ranging from 1.9 to 2.4 µM) is revealed. The anti-ACE effect (12.3 µg/mL; 91.2% inhibition) is also ascertained. Molecular docking analyses propose that the mechanisms by which brassicasterol induces anti-HSV-1 and anti-Mtb might be related to inhibiting vital enzymes involved in HSV-1 replication and Mtb cell wall biosynthesis. In summary, the obtained results suggest that brassicasterol might be promising for future anti-HSV-1, antituberculosis, and anti-ACE drug design.

• Keywords
• ACE, HSV, HSV-1 DNA polymerase, HSV-1 TK, Mycobacterium tuberculosis, UDP-galactopyranose mutase, brassicasterol, human CDK2, phytosterols,
• Publication type
• Journal Article MeSH

The whole world is currently facing an unseen enemy, called coronavirus disease 2019 (COVID-19), which is causing a global pandemic. This disease is caused by a novel single-stranded enveloped RNA virus, known as the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Although huge efforts are being made to produce effective therapies to combat this disease, it continues to be one of the greatest challenges in medicine. There is no doubt that herpesviruses are one of the most important viruses that infect humans and animals, and infections induced by these pathogens have developed into a great threat to public health. According to the currently available evidence, the correlation between herpesviruses and coronaviruses is limited to the induced complications following the infections. For instance, the inflammation that is induced at the sites of infection could tie these viruses to each other in a relationship. Another example, bovine herpesvirus 1, which is an important pathogen of cattle, can cause a severe respiratory infection; the same way in which SARS-CoV-2 affects humans. Considering the current circumstances related to the COVID-19 crisis, this editorial paper, which belongs to the Special Issue "Recent Advances in Herpesviruses Research: What's in the Pipeline?" aims to draw attention to some natural anti-herpesvirus alkaloid compounds, which have recently been proven to have excellent inhibitory efficacy against SARS-CoV-2 replication. Thus, this special focus is an attempt to hunt down various treatment options to combat COVID-19 based on repurposing drugs that are known to have multiple antiviral properties, including against herpesvirus.

• Keywords
• COVID-19, SARS-CoV-2, alkaloids, anti-herpesvirus drugs, herpesviruses,
• MeSH
• Alkaloids pharmacology   MeSH
• Antiviral Agents pharmacology   MeSH
• Betacoronavirus drug effects   MeSH
• COVID-19 MeSH
• Herpesviridae drug effects   MeSH
• Herpesviridae Infections drug therapy   MeSH
• Coronavirus Infections drug therapy   MeSH
• Humans MeSH
• Pandemics MeSH
• Plant Extracts pharmacology   therapeutic use   MeSH
• SARS-CoV-2 MeSH
• Pneumonia, Viral drug therapy   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Editorial MeSH
• Names of Substances
• Alkaloids MeSH
• Antiviral Agents MeSH
• Plant Extracts MeSH

Recently, the problem of viral infection, particularly the infection with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), has dramatically increased and caused a significant challenge to public health due to the rising problem of drug resistance. The antiherpetic drug resistance crisis has been attributed to the overuse of these medications, as well as the lack of new drug development by the pharmaceutical industry due to reduced economic inducements and challenging regulatory requirements. Therefore, the development of novel antiviral drugs against HSV infections would be a step forward in improving global combat against these infections. The incorporation of biologically active natural products into anti-HSV drug development at the clinical level has gained limited attention to date. Thus, the search for new drugs from natural products that could enter clinical practice with lessened resistance, less undesirable effects, and various mechanisms of action is greatly needed to break the barriers to novel antiherpetic drug development, which, in turn, will pave the road towards the efficient and safe treatment of HSV infections. In this review, we aim to provide an up-to-date overview of the recent advances in natural antiherpetic agents. Additionally, this paper covers a large scale of phenolic compounds, alkaloids, terpenoids, polysaccharides, peptides, and other miscellaneous compounds derived from various sources of natural origin (plants, marine organisms, microbial sources, lichen species, insects, and mushrooms) with promising activities against HSV infections; these are in vitro and in vivo studies. This work also highlights bioactive natural products that could be used as templates for the further development of anti-HSV drugs at both animal and clinical levels, along with the potential mechanisms by which these compounds induce anti-HSV properties. Future insights into the development of these molecules as safe and effective natural anti-HSV drugs are also debated.

• Keywords
• antiherpetic drugs, bioactive natural products, drug development, drug resistance, herpes simplex virus infection, mechanisms of action, preclinical and clinical studies,
• MeSH
• Antiviral Agents chemistry   pharmacology   MeSH
• Biological Products chemistry   pharmacology   MeSH
• Drug Industry MeSH
• Humans MeSH
• Herpesvirus 1, Human drug effects   MeSH
• Herpesvirus 2, Human drug effects   MeSH
• Drug Discovery * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antiviral Agents MeSH
• Biological Products MeSH

A series of sixteen ring-substituted N-arylcinnamanilides, previously described as highly antimicrobially effective against a wide spectrum of bacteria and fungi, together with two new derivatives from this group were prepared and characterized. Moreover, the molecular structure of (2E)-N-(2-bromo-5-fluorophenyl)-3-phenylprop-2-enamide as a model compound was determined using single-crystal X-ray analysis. All the compounds were tested for their anti-inflammatory potential, and most tested compounds significantly attenuated the lipopolysaccharide-induced NF-κB activation and were more potent than the parental cinnamic acid. (2E)-N-[2-Chloro-5-(trifluoromethyl)phenyl]-3-phenylprop-2-enamide, (2E)-N-(2,6-dibromophenyl)- 3-phenylprop-2-enamide, and (2E)-N-(2,5-dichlorophenyl)-3-phenylprop-2-enamide demonstrated the highest inhibition effect on transcription factor NF-κB at the concentration of 2 µM and showed a similar effectiveness as the reference drug prednisone. Several compounds also decreased the level of TNF-α. Nevertheless, subsequent tests showed that the investigated compounds affect neither IκBα level nor MAPKs activity, which suggests that the N-arylcinnamanilides may have a different mode of action to prednisone. The modification of the C(2,5)' or C(2,6)' positions of the anilide core by rather lipophilic and bulky moieties seems to be preferable for the anti-inflammatory potential of these compounds.

• Keywords
• X-ray structure, anti-inflammatory potential, cinnamamides, polypharmacology,
• MeSH
• Anti-Inflammatory Agents chemical synthesis   chemistry   pharmacology   MeSH
• Cinnamates chemical synthesis   chemistry   pharmacology   MeSH
• Crystallography, X-Ray MeSH
• Humans MeSH
• Lipopolysaccharides adverse effects   MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• NF-kappa B metabolism   MeSH
• Gene Expression Regulation drug effects   MeSH
• Signal Transduction drug effects   MeSH
• THP-1 Cells MeSH
• Tumor Necrosis Factor-alpha metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Inflammatory Agents MeSH
• Cinnamates MeSH
• Lipopolysaccharides MeSH
• NF-kappa B MeSH
• TNF protein, human MeSH Browser
• Tumor Necrosis Factor-alpha MeSH

Psoromic acid (PA), a bioactive lichen-derived compound, was investigated for its inhibitory properties against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), along with the inhibitory effect on HSV-1 DNA polymerase, which is a key enzyme that plays an essential role in HSV-1 replication cycle. PA was found to notably inhibit HSV-1 replication (50% inhibitory concentration (IC50): 1.9 μM; selectivity index (SI): 163.2) compared with the standard drug acyclovir (ACV) (IC50: 2.6 μM; SI: 119.2). The combination of PA with ACV has led to potent inhibitory activity against HSV-1 replication (IC50: 1.1 µM; SI: 281.8) compared with that of ACV. Moreover, PA displayed equivalent inhibitory action against HSV-2 replication (50% effective concentration (EC50): 2.7 μM; SI: 114.8) compared with that of ACV (EC50: 2.8 μM; SI: 110.7). The inhibition potency of PA in combination with ACV against HSV-2 replication was also detected (EC50: 1.8 µM; SI: 172.2). Further, PA was observed to effectively inhibit HSV-1 DNA polymerase (as a non-nucleoside inhibitor) with respect to dTTP incorporation in a competitive inhibition mode (half maximal inhibitory concentration (IC50): 0.7 μM; inhibition constant (Ki): 0.3 μM) compared with reference drugs aphidicolin (IC50: 0.8 μM; Ki: 0.4 μM) and ACV triphosphate (ACV-TP) (IC50: 0.9 μM; Ki: 0.5 μM). It is noteworthy that the mechanism by which PA-induced anti-HSV-1 activity was related to its inhibitory action against HSV-1 DNA polymerase. Furthermore, the outcomes of in vitro experiments were authenticated using molecular docking analyses, as the molecular interactions of PA with the active sites of HSV-1 DNA polymerase and HSV-2 protease (an essential enzyme required for HSV-2 replication) were revealed. Since this is a first report on the above-mentioned properties, we can conclude that PA might be a future drug for the treatment of HSV infections as well as a promising lead molecule for further anti-HSV drug design.

• Keywords
• HSV, HSV replication, anti-enzymatic properties, antiherpetic, lichen metabolites, psoromic acid,
• MeSH
• Antiviral Agents * chemistry   pharmacology   MeSH
• Benzoxepins * chemistry   pharmacology   MeSH
• Chlorocebus aethiops MeSH
• DNA-Directed DNA Polymerase * chemistry   metabolism   MeSH
• Nucleic Acid Synthesis Inhibitors chemistry   pharmacology   MeSH
• Carboxylic Acids * chemistry   pharmacology   MeSH
• Humans MeSH
• Herpesvirus 1, Human physiology   MeSH
• Herpesvirus 2, Human physiology   MeSH
• Lichens chemistry   MeSH
• Virus Replication drug effects   MeSH
• Molecular Docking Simulation * MeSH
• Vero Cells MeSH
• Viral Proteins * antagonists & inhibitors   chemistry   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antiviral Agents * MeSH
• Benzoxepins * MeSH
• DNA-Directed DNA Polymerase * MeSH
• Nucleic Acid Synthesis Inhibitors MeSH
• Carboxylic Acids * MeSH
• psoromic acid MeSH Browser
• Viral Proteins * MeSH