Herpes simplex virus (HSV) is a prevalent and persistent human pathogen belonging to the family Herpesviridae and classified as an alpha-herpesvirus. It comprises two distinct types, HSV-1 and HSV-2, which together infect a significant portion of the global population and pose substantial public health challenges. HSV-1 is typically associated with oral herpes, while HSV-2 primarily causes genital herpes; both are characterized by recurrent lesions, latent infection, and mucocutaneous discomfort. Conventional antiviral drugs such as acyclovir and its derivatives are limited by drug resistance, potential toxicity, and their inability to eradicate latent viral reservoirs. These limitations have prompted increasing interest in alternative therapeutic strategies. Phenolic acids and tannins, plant-derived polyphenolic compounds, have attracted considerable attention due to their potent antiviral properties against various viruses, including HSV. This review summarizes current research on phenolic acids and tannins as promising natural antivirals against HSV, with a focus on their mechanisms of action and efficacy in disrupting multiple stages of the HSV life cycle.

• Keywords
• HSV latency, acyclovir resistance, antiviral mechanisms, herpes simplex virus, herpesvirus infections, natural antivirals, phenolic acids, polyphenols, synergistic antiviral effects, tannins,
• MeSH
• Antiviral Agents * pharmacology   therapeutic use   chemistry   MeSH
• Herpes Simplex * drug therapy   virology   MeSH
• Hydroxybenzoates * pharmacology   chemistry   therapeutic use   MeSH
• Humans MeSH
• Herpesvirus 1, Human * drug effects   physiology   MeSH
• Herpesvirus 2, Human drug effects   MeSH
• Virus Replication drug effects   MeSH
• Simplexvirus * drug effects   physiology   MeSH
• Tannins * pharmacology   chemistry   therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antiviral Agents * MeSH
• Hydroxybenzoates * MeSH
• phenolic acid MeSH Browser
• Tannins * MeSH

Herpesviruses are one of the most contagious DNA viruses that threaten human health, causing severe diseases, including, but not limited to, certain types of cancer and neurological complications. The overuse and misuse of anti-herpesvirus drugs are key factors leading to drug resistance. Therefore, targeting human herpesviruses with natural products is an attractive form of therapy, as it might improve treatment efficacy in therapy-resistant herpesviruses. Plant polyphenols are major players in the health arena as they possess diverse bioactivities. Hence, in this article, we comprehensively summarize the recent advances that have been attained in employing plant non-flavonoid polyphenols, such as phenolic acids, tannins and their derivatives, stilbenes and their derivatives, lignans, neolignans, xanthones, anthraquinones and their derivatives, curcuminoids, coumarins, furanocoumarins, and other polyphenols (phloroglucinol) as promising anti-herpesvirus drugs against various types of herpesvirus such as alpha-herpesviruses (herpes simplex virus type 1 and 2 and varicella-zoster virus), beta-herpesviruses (human cytomegalovirus), and gamma-herpesviruses (Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus). The molecular mechanisms of non-flavonoid polyphenols against the reviewed herpesviruses are also documented.

• Keywords
• Epstein–Barr virus (EBV), HSV-1, HSV-2, Kaposi sarcoma-associated herpesvirus (KSHV), antiviral activity, herpes simplex virus, human cytomegalovirus (HCMV), natural products, non-flavonoid polyphenols, polyphenols, varicella-zoster virus (VZV),
• MeSH
• Antiviral Agents pharmacology   therapeutic use   MeSH
• Herpesviridae Infections * drug therapy   MeSH
• Epstein-Barr Virus Infections * drug therapy   MeSH
• Humans MeSH
• Polyphenols pharmacology   therapeutic use   MeSH
• Herpesvirus 4, Human MeSH
• Herpesvirus 3, Human MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antiviral Agents MeSH
• Polyphenols 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

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

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

In the current study, pyroglutamic acid (pGlu), a natural amino acid derivative, has efficiently inhibited the catalytic activities of three important enzymes, namely: Human recombinant phosphodiesterase-5A1 (PDE5A1), human angiotensin-converting enzyme (ACE), and urease. These enzymes were reported to be associated with several important clinical conditions in humans. Radioactivity-based assay, spectrophotometric-based assay, and an Electrospray Ionization-Mass Spectrometry-based method were employed to ascertain the inhibitory actions of pGlu against PDE5A1, ACE, and urease, respectively. The results unveiled that pGlu potently suppressed the activity of PDE5A1 (half-maximal inhibitory concentration; IC50 = 5.23 µM) compared with that of standard drug sildenafil citrate (IC50 = 7.14 µM). Moreover, pGlu at a concentration of 20 µg/mL was found to efficiently inhibit human ACE with 98.2% inhibition compared with that of standard captopril (99.6%; 20 µg/mL). The urease-catalyzed reaction was also remarkably inactivated by pGlu and standard acetohydroxamic acid with IC50 values of 1.8 and 3.9 µM, respectively. Remarkably, the outcome of in vitro cytotoxicity assay did not reveal any significant cytotoxic properties of pGlu against human cervical carcinoma cells and normal human fetal lung fibroblast cells. In addition to in vitro assays, molecular docking analyses were performed to corroborate the outcomes of in vitro results with predicted structure-activity relationships. In conclusion, pGlu could be presented as a natural and multifunctional agent with promising applications in the treatment of some ailments connected with the above-mentioned anti-enzymatic properties.

• Keywords
• ESI-mass spectrometry, angiotensin-converting enzyme, anti-enzymatic properties, cytotoxicity, phosphodiesterase 5, pyroglutamic acid, urease,
• MeSH
• Peptidyl-Dipeptidase A chemistry   genetics   metabolism   MeSH
• Cell Line MeSH
• Cyclic Nucleotide Phosphodiesterases, Type 5 chemistry   genetics   metabolism   MeSH
• Spectrometry, Mass, Electrospray Ionization MeSH
• Inhibitory Concentration 50 MeSH
• Captopril chemistry   metabolism   MeSH
• Pyrrolidonecarboxylic Acid chemistry   metabolism   toxicity   MeSH
• Hydroxamic Acids antagonists & inhibitors   metabolism   MeSH
• Humans MeSH
• Recombinant Proteins biosynthesis   chemistry   isolation & purification   MeSH
• Sildenafil Citrate chemistry   metabolism   MeSH
• Molecular Docking Simulation MeSH
• Spectrophotometry MeSH
• Protein Structure, Tertiary MeSH
• Urease antagonists & inhibitors   metabolism   MeSH
• Binding Sites MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• ACE protein, human MeSH Browser
• acetohydroxamic acid MeSH Browser
• Peptidyl-Dipeptidase A MeSH
• Cyclic Nucleotide Phosphodiesterases, Type 5 MeSH
• Captopril MeSH
• Pyrrolidonecarboxylic Acid MeSH
• Hydroxamic Acids MeSH
• PDE5A protein, human MeSH Browser
• Recombinant Proteins MeSH
• Sildenafil Citrate MeSH
• Urease 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

Thymus bovei Benth. (TB) is an important plant in the traditional medicine of the Mediterranean region. This study investigates the health-promoting properties of TB essential oil (TB-EO) for its possible use in clinical practice with regards to its cytotoxic, anti-herpes simplex virus type 2 (HSV-2), and antihypertensive (through inhibition of human angiotensin-converting enzyme; ACE) properties. The phytochemical profile of EO (99.9%) was analyzed by Gas Chromatography with Flame-Ionization Detection (GC-FID) and Gas Chromatography-Mass Spectrometry (GC-MS). In this study, all biological methods were performed at the level of in vitro studies. The results showed that TB-EO exerted remarked cytotoxic properties against human cervical carcinoma cells, colon cancer cells, and lung adenocarcinoma cells with the half-maximal inhibitory concentration (IC50) values of 7.22, 9.30, and 8.62 µg/mL, respectively, in comparison with that of standard anticancer drug cisplatin with IC50 values of 4.24, 5.21, and 5.43 µg/mL, respectively. Fascinatingly, TB-EO showed very weak cytotoxicity on the healthy human fetal lung fibroblast cells with an IC50 value of 118.34 µg/mL compared with that of cisplatin (IC50 = 10.08 µg/mL). TB-EO, its main component geraniol, TB-EO combined with acyclovir (ACV) along with standard ACV, have displayed pronounced inhibitory properties against the replication of HSV-2 with the half-maximal effective concentration (EC50) values of 2.13, 1.92, 0.81 and 1.94 µg/mL, respectively, with corresponding selectivity indices (SI) 98.59, 109.38, 259.26 and 108.25, respectively. TB-EO and geraniol at a concentration of 15 µg/mL showed prominent inhibitory activities against ACE with % of inhibition 95.4% and 92.2%, respectively, compared with that of standard inhibitor captopril (99.8%; 15 µg/mL). Molecular docking studies were performed to unveil the mechanism of action of geraniol as well as structural parameters necessary for anti-HSV-2 activity (through the inhibition of HSV-2 protease) and ACE inhibition. This is the first report on the chemical composition of Egyptian TB-EO along with the above-mentioned biological activities. Our results may be considered as novel findings in the course of a search for new and active anticancer, anti-HSV-2 and antihypertensive agents, and expand the medicinal value of this plant and its phytochemicals in clinical practice.

• Keywords
• HSV-2, Thymus bovei Benth., anticancer, antihypertensive, essential oil, phytochemical profile,
• Publication type
• Journal Article MeSH

Herpes simplex virus (HSV) causes numerous mild-to-serious human diseases, including mucocutaneous herpes infections and life-threatening herpes encephalitis. Moreover, herpes viral lesions can be complicated by inflammation and secondary bacterial infections. The development of resistance to antiviral drugs along with the undesirable side effects of these drugs are relevant argue for the development of new anti-HSV drugs with diverse mechanisms of action. Eucalyptus extracts have been used for decades to combat various infectious diseases. We isolated and studied 12 pure compounds and one mixture of two constitutional isomers from the leaves and twigs of E. globulus. The structures were identified by spectroscopic methods (NMR, HR-MS, IR) and all of them were tested for antiherpetic activity against the replication of antigen types HSV-1 and HSV-2. Tereticornate A (12) (IC50: 0.96 μg/mL; selectivity index CC50/IC50: 218.8) showed the strongest activity in the anti-HSV-1 assay, even greater than acyclovir (IC50: 1.92 μg/mL; selectivity index CC50/IC50: 109.4), a standard antiviral drug. Cypellocarpin C (5) (EC50: 0.73 μg/mL; selectivity index CC50/EC50: 287.7) showed the most potent anti-HSV-2 activity, also more intensive than acyclovir (EC50: 1.75 μg/mL; selectivity index CC50/EC50: 120.0). The antimicrobial activity of the isolated compounds was also evaluated against the bacteria Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa and the yeast Candida albicans. The anti-inflammatory potential was examined using LPS-stimulated THP-1-XBlue™-MD2-CD14 and THP-1 macrophages and focusing on the influences of the NF-κB/AP-1 activity and the secretion of pro-inflammatory cytokines IL-1β and TNF-α.

• Keywords
• Eucalyptus, HSV-1, HSV-2, IL-1β, NF-κB/AP-1, ROS, TNF-α, anti-inflammatory, antibacterial, antiherpetic,
• MeSH
• Anti-Bacterial Agents chemistry   pharmacology   MeSH
• Anti-Inflammatory Agents chemistry   pharmacology   MeSH
• Anti-Infective Agents chemistry   pharmacology   MeSH
• Antioxidants metabolism   MeSH
• Antiviral Agents chemistry   pharmacology   MeSH
• Cell Line MeSH
• Chlorocebus aethiops MeSH
• Cytokines metabolism   MeSH
• Eucalyptus chemistry   MeSH
• Herpes Simplex metabolism   virology   MeSH
• Humans MeSH
• NF-kappa B metabolism   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Plant Extracts chemistry   pharmacology   MeSH
• Simplexvirus drug effects   physiology   MeSH
• Transcription Factor AP-1 metabolism   MeSH
• Vero Cells MeSH
• Cell Survival drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Anti-Inflammatory Agents MeSH
• Anti-Infective Agents MeSH
• Antioxidants MeSH
• Antiviral Agents MeSH
• Cytokines MeSH
• NF-kappa B MeSH
• Reactive Oxygen Species MeSH
• Plant Extracts MeSH
• Transcription Factor AP-1 MeSH