Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development

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.


Introduction
Infection with herpes simplex virus (HSV) has been recognized since antiquity in humans, however, the first in vitro cultivation of HSV was assayed in 1925 [1]. Since 1968, herpes simplex type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) have been distinguished from each other by different clinical manifestations and tropism [2]. HSV belongs to Herpesviridae, which is a broad family of enveloped-DNA viruses that induce numerous clinically substantial syndromes in both adults and neonates. Several factors including viral entrance, the nature of the disease, and degree of host immune competency could affect the induced syndromes [3,4]. HSV-1 is generally associated with oral or facial infection and encephalitis, while HSV-2 is accountable for genital herpes, which is an important sexually transmitted disease [5]. Moreover, infection with HSV-2 can cause recurrent, painful genital lesions and is often connected with negative psychosocial consequences such as shame, anxiety, and depression. Furthermore, infection with HSV-2 was observed to be a high-risk factor for potential HIV infection, as well as invasive cervical carcinoma [6]. Several reports have declared that HSV is involved in various ocular diseases, including stromal keratitis, endotheliitis and neurotrophic keratopathy [4][5][6][7]. The current existant treatment of HSV infection relies mainly on the use of acyclovir (ACV) and related synthetic nucleoside analogs. Unfortunately, the rigorous utilization of these drugs has led to the establishment of undesirable effects as well as drug-resistant strains [8,9]. Although imperative efforts were taken to develop a vaccination, no vaccines have been validated or marketed for effective prevention of the infection to date. Therefore, the development of new antiviral medications has earned much attention in recent decades [10,11]. While many anti-HSV drugs have already been developed and engaged in the treatment of HSV infections, the search for different sources of anti-HSV drugs is a great task for many researchers and healthcare providers to conquer challenges with drug resistance [12]. Thus, it is an important concern to open new gates to search for new therapeutic agents that perform with different mechanisms of action than nucleoside analogs. Nature is a very rich source of these molecules.

Epidemiology and Pathogenesis of HSV Infection
It's acknowledged that HSV endures for the lifetime of the host in the form of latent infection in the peripheral neurons [13]. After infection begins, reactivation can be systematically triggered by re-entering the lytic phase of replication to create a progeny virus for spreading [14]. However, during latent infection, the viral lytic genes are largely down-regulated, and their promoters are joined into repressive heterochromatin ( Figure 1). Consequently, reactivation necessitates viral lytic gene expression to be created by silenced promoters in the absence of viral proteins [15]. During primary infection, HSV penetrates through breaks in the skin or mucosa and subsequently attaches to and accesses epithelial cells and starts replication. It's taken up by free sensory nerve endings placed at the dermis, and the nucleocapsid containing the viral genome is transferred by retrograde axonal flow to the nucleus in the sensory ganglion [16,17]. Skin symptoms include vesicular lesions on an erythematous base. Lesions drive to the focal damage of the epithelial layer and a widespread infiltrate of inflammatory cells elaborates in the surrounding rim and the underlying dermal layer [15,18]. It has been estimated that 10-30% of new infections are symptomatic. After recovering from the initial infection, HSV perseveres latently in the sensory ganglion for the life of the host. Regularly, the virus reactivates from the latent state and moves back down the sensory nerves to the skin or mucosal surface [15,19]. Viral shedding can appear either in the presence of lesions as a clinical reactivation or with very moderate or no symptoms as subclinical reactivation. Shedding from mucosal surfaces drives transmission to other sexual partners and, in some cases, infection with HSV can be transferred from mother to infant at delivery [20,21].

Natural Products-Derived Molecules with Anti-HSV-1 and Anti-HSV-2 Properties
As a part of our ongoing search for natural compounds that are effective against HSV infection, we tried to evaluate progress by reviewing the compounds showing promising anti-herpetic activities. The reviews of the literature covering this area were published previously [22][23][24], with the latest in 2015 [25]. Thus, we followed the latest information and gathered approximately 83 literature sources, which were not included in these papers, showing natural compounds with anti-HSV activity. The SciFinder database was used to cover this area of the published literature and selected data for compounds obtained by the search are presented in Tables 1-6

Natural Products-Derived Molecules with Anti-HSV-1 and Anti-HSV-2 Properties
As a part of our ongoing search for natural compounds that are effective against HSV infection, we tried to evaluate progress by reviewing the compounds showing promising anti-herpetic activities. The reviews of the literature covering this area were published previously [22][23][24], with the latest in 2015 [25]. Thus, we followed the latest information and gathered approximately 83 literature sources, which were not included in these papers, showing natural compounds with anti-HSV activity. The SciFinder database was used to cover this area of the published literature and selected data for compounds obtained by the search are presented in Tables 1-6 and Figures 2-5. Dietary phenolics, green tea, propolis, some flavonoid rich medicinal plants. Flavanols and flavonols appear to be more active than flavones. Furthermore, treatment of Vero cells with ECG (8) and galangin (11) before virus adsorption led to a slight enhancement of inhibition, indicating that an intracellular effect may be involved. [27] Baicalin (   Study of synergy with ACV and inhibition of HSV-1 DNA polymerase (in vitro and in silico assays). [46]

Rhinacanthinic acid C (46)
Vero cells, HSV-2 PRA ACV ED 50  51 did not inactivate cell-free HSV-1 particles but inhibited cellular adsorption and penetration of HSV-1 viral particles. Following viral penetration, 51 reduced the expression of HSV-1 IE and L genes and decreased the synthesis of HSV-1 DNA. Furthermore, 51 inhibited the HSV-1-induced nuclear factor (NF)-κB activation through blocking the nuclear translocation and DNA binding of NF-κB. [50]

Compound
Antiherpetic and Cytotoxicity Assays, Strains, Cells, and Reference Agents

Compound
Antiherpetic and Cytotoxicity Assays, Strains, Cells, and Reference Agents

Additional Information Source
Pentacyclic triterpenes

Natural Products Targeting Enzymes Implicated in HSV Replication
Over the past few decades, structural and mechanistic enzymology played a central role in virology research, where a wide range of enzymes that play a vital role in viral replication, viral transcription or have an impact on the pathogenesis of infection have become imperative drug targets for therapeutic intervention [117,118]. Recently,Čulenová et al. [34] have isolated phenolic compounds from Morus alba root bark, kuwanon C (22), kuwanon T (23), kuwanon U (24) and ethyl 2,4-dihydroxybenzoate (37) with clear inhibitory action against HSV-1, with IC 50 values ranging from 0.64 to 1.93 µ/mL, while kuwanon E (25) and mulberrofuran B (52) inhibited effectively the replication of HSV-2, with EC 50 values of 0.93 and 1.61 µg/mL, respectively. Molecular docking analysis outcomes proved the effects of the active compounds by targeting the HSV-1 DNA polymerase and HSV-2 protease (proposed as competitive inhibitors), which are crucial enzymes that display an important role in the HSV replication cycle.
Geraniol (62), a monoterpenoid active compound detected in Thymus bovei Benth. essential oil has shown to possess obvious inhibitory effects on HSV-2 replication (EC 50 = 1.92 µg/mL; SI = 109.38) compared with that of standard ACV (EC 50 = 1.94 µg/mL; SI = 108.25). This substance, in a molecular docking analysis, has proved to bind to the active site of HSV-2 protease as a competitive inhibitor, and hence uncovered the potential mechanism of action behind the antiherpetic properties against HSV-2 ( Figure 6) [57].

Natural Products Targeting Enzymes Implicated in HSV Replication
Over the past few decades, structural and mechanistic enzymology played a central role in virology research, where a wide range of enzymes that play a vital role in viral replication, viral transcription or have an impact on the pathogenesis of infection have become imperative drug targets for therapeutic intervention [117,118]. Recently, Čulenová et al. [34] have isolated phenolic compounds from Morus alba root bark, kuwanon C (22), kuwanon T (23), kuwanon U (24) and ethyl 2,4-dihydroxybenzoate (37) with clear inhibitory action against HSV-1, with IC50 values ranging from 0.64 to 1.93 μ/mL, while kuwanon E (25) and mulberrofuran B (52) inhibited effectively the replication of HSV-2, with EC50 values of 0.93 and 1.61 μg/mL, respectively. Molecular docking analysis outcomes proved the effects of the active compounds by targeting the HSV-1 DNA polymerase and HSV-2 protease (proposed as competitive inhibitors), which are crucial enzymes that display an important role in the HSV replication cycle.
Additionally, molecular docking investigation has revealed the potential mechanism underlying the anti-HSV-2 property of 45 by targeting HSV-2 protease (competitive inhibitor) (Figure 8). Additionally, molecular docking investigation has revealed the potential mechanism underlying the anti-HSV-2 property of 45 by targeting HSV-2 protease (competitive inhibitor) (Figure 8).   Additionally, molecular docking investigation has revealed the potential mechanism underlying the anti-HSV-2 property of 45 by targeting HSV-2 protease (competitive inhibitor) (Figure 8).

General Discussion
In general, from the data analysis, we cannot merely conclude with any broad recommendation for further phytochemical research on specific plant family or genus, just some limited hints connected to specific groups of compounds or plant species. First, we have to mention that there is a relative lack of information concerning in vivo testing of compounds assayed in the Vero cell model system against HSV, as described, for example, here [119]. The methodology for testing in vitro anti-HSV activity is commonly based on the assays using the Vero cell line (kidney epithelial cells extracted from an African green monkey (Chlorocebus sp.). Vero cells are widely acknowledged to be well-suited for testing antiviral activity, as these cells do not secrete interferon α or β as a response to viral infection, while possessing the INF-α/β receptors, and therefore behave normally after the addition of exogenous interferon [120]. The overall stability and susceptibility of Vero cells to many pathogens, including HSV, makes these cells a very useful tool for testing new potential anti-HSV compounds.
The methodology for testing the anti-HSV activity used in the covered literature search is relatively uniform, allowing the detection of potential hits and finding candidates for antiviral research [121]. The main methods used are analyses of the viability of infected and non-infected cells, the plaque reduction assay, virus cytopathic effect monitoring [122], real-time PCR, quantification of intracellular viral DNA load [123] and the following calculation of selectivity indices. Virus multiplication can also be monitored by ELISA analysis of antigen expression in cell culture. Modifications of these methods, using the sophisticated timing of anti-HSV drug candidate application and further analysis, can give additional information about HSV attachment and penetration to cells [124,125].
The very common therapeutic standard used as the positive control of anti-HSV assays is acyclovir [126]. As it is evident from our literature search and other materials, both HSV-1 and HSV-2, including clinical strains, are sensitive to acyclovir when propagated in Vero cells, with IC 50 values at low-micromolar concentrations (or micrograms per mL) and selectivity indices reaching values up to 1000 or greater.
According to our literature research, there is an interest in finding new or alternative anti-HSV compounds, represented, for example, by the above-mentioned review published in 2015 [25]. We organized an additional search for anti-HSV natural compounds and gathered information about approximately 100 low-molecular secondary metabolites, obtained from both plants and marine organisms, and also high-molecular polymers represented by a number of sulfated polysaccharides, mainly from marine organisms (algal compounds) and peptides of mainly microbial origin.
Within the compounds mentioned, the most frequent groups with anti-HSV properties are groups of phenolic compounds, comprising a set of simple phenols, flavonoids (mainly dietary flavonoids) and tannins (Table 1). Based on the results of the concurrent analysis and a comparison with previously summarized reports about anti-HSV-activity [22][23][24][25], we can conclude that tannins possess activity comparable to standard acyclovir. Compounds 40 and 41 show activity almost 20× greater and can possibly prevent the attachment of viral particles to the cells and stop the virus' penetration into the cell [43]. Similarly, some flavonoid aglycones displayed promising results, showing greater effects than acyclovir and greater selectivity. Moreover, according to our recent findings, we can deduce that flavanols are showing greater activity than flavones. This beneficial effect could be possibly subscribed to the 3-OH hydroxy substitution [27]. Furthermore, the treatment of cells with epicatechin gallate (8) and galangin (11) before HSV adsorption led to some increase in inhibition as determined, indicating that an intracellular activity against the virus may also be involved.
The dual antiviral and antibacterial activity can be beneficial, for example, in the treatment of oral or labial herpetic lesions, which can be relatively easily complicated by secondary bacterial infections. From Table 1, we can deduce that one of the most active phenolic compounds against HSV-1 was kuwanon T (23), with IC 50 0.64 µg/mL (corresponding to 1.5 µM) and SI 328.1. Kuwanon T (23) has also shown promising antibacterial activity against several Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis. The MIC values of compound 23 ranged from 4-8 µg/mL which exceeded the activity of standard antibiotics ampicillin and ciprofloxacin [34]. Another promising phenolic compound against HSV-1 is galangin (11), with IC 50 2.5 µM and SI 400. Further, galangin (11) has shown bacteriostatic activity against S. aureus (ATCC 25293) with MIC value 32 µg/mL [127]. Another phenolic with equal antiviral activity-naringin (17)-showed no inhibitory effect on several Gram-positive and Gram-negative, even at a concentration of 250 µM [128]. This dual ability or disability can therefore be a secondary criterion for the potential use of natural anti-herpetic compounds and further research on their activity.
Cucurbitacin B (94) is one of the most potent antiviral triterpenoids (IC 50 = 0.94 µM and SI = 127.7), as shown in Table 3. This compound is also a very effective antibacterial agent-its MIC values against S. aureus and MRSA were found to be 0.20 and 0.12 µg/mL, respectively [73]. However, cypellocarpin C (63), an effective terpenoid molecule against HSV-2 with IC 50 = 0.73 µg/mL and SI > 287.7, did not show any antibacterial activity against several Gram-positive and Gram-negative bacteria [58], and, as in the case of phenolics, this can be a selective criterion for further research.
Polysaccharides, heterogeneous natural compounds with promising anti-HSV activity, were reviewed in 2009 [129]. Many of them were isolated from marine seaweeds, especially Chromophyta (brown algae) and Rhodophyta (red algae), and their anti-HSV activities were evaluated and confirmed recently (as visible in Table 5). From the structural point of view, most of them are sulfated polysaccharides with a different degree of sulphation. The degree of sulphation was found to be important for the anti-HSV effect, however, a question remains around the anticoagulant activity of such compounds. Several studies found no correlation between anticoagulant and antiviral activity of sulphated polysaccharides, and such activity would be clinically important only after absorption of the compound into an organism, not during local application. The benefit of anti-HSV polysaccharides can be observed (when measured and calculated) in their high selectivity index. The examples of promising compounds can be partially cyclized µ/v-carrageenan from red seaweed Gigartina skottsbergii [101], sulfated galactans from Schizymenia binderi [100], and nostoflan, the acidic polysaccharide from terrestrial cyanobacterium Nostoc flagelliforme [106].
The last separated reviewed group of compounds are peptides, obtained from various sources, including bacteria, deep-sea fungi, or edible mushrooms. Griffithsin, isolated from red alga Griffithsia (family Wrangeliaceae), appears to be very effective against HSV-2, with effects at submicromolar concentrations. Furthermore, griffithsin can be possibly combined with carrageenan and effectively used topically in vivo [115]. Among the potent antiviral peptides against HSV-1 is also melittin, with IC 50 1.35 µM and SI 6.3. This peptide acts also as antibacterial-when MRSA was treated with melittin at a concentration of 25 µg/mL, the total number of bacteria decreased by~2.5-3 log CFU [130].
From the reviewed articles, all potential mechanisms by which natural products-derived chemicals induced anti-HSV properties have been documented and highlighted, as shown in Figure 9. In the reviewed articles, the majority of assays were basically performed to evaluate the concentration of test compounds necessary to reduce the number of plaques formed in cells and to calculate the selectivity index from the corresponding cytotoxic effect of the test compound on Vero cells. For some compounds, authors performed additional assays to gain deeper insight into the mechanism of action. As an example, chebulagic acid (40) and chebulinic acid (41) were observed to prevent the attachment and penetration of HSV-2 into Vero cells [43]. Curcumin (56) was detected to inhibit HSV adsorption and replication [51], while houttuynoid A (21) was noted to block viral membrane fusion [32]. Another good example is the research on prenylated phenol kuwanon X (51) [50]. Compound 51 did not inactivate cell-free HSV-1 but inhibited the cellular adsorption and penetration of HSV-1 viral particles. Following viral penetration, 51 reduced the expression of HSV-1 IE and L genes and decreased the synthesis of HSV-1 DNA. Furthermore, 51 inhibited the HSV-1-induced nuclear factor (NF)-κB activation through blocking the nuclear translocation and DNA binding of NF-κB. The study of Lee et al. [28] gave some insight into the effect of flavonoids, showing the ability of quercetin (19), a "prototype" of flavonoid, to inhibit the expressions of HSV proteins (gD, ICP0) and genes (ICP0, UL13, UL52), and specifically suppress the expression of TLR-3 and inhibit the transcription factors NF-κB and IRF3 [28]. The antiviral activity of halistanol derivatives (96 and 97) against HSV-1 is enabled by the inhibition of viral particles' attachment and penetration; the virucidal effect was also observed. Further analysis showed changes in the levels of proteins ICP27 and the gD of HSV-1. These compounds also act synergistically or with acyclovir [74]. concentration of test compounds necessary to reduce the number of plaques formed in cells and to calculate the selectivity index from the corresponding cytotoxic effect of the test compound on Vero cells. For some compounds, authors performed additional assays to gain deeper insight into the mechanism of action. As an example, chebulagic acid (40) and chebulinic acid (41) were observed to prevent the attachment and penetration of HSV-2 into Vero cells [43]. Curcumin (56) was detected to inhibit HSV adsorption and replication [51], while houttuynoid A (21) was noted to block viral membrane fusion [32]. Another good example is the research on prenylated phenol kuwanon X (51) [50]. Compound 51 did not inactivate cell-free HSV-1 but inhibited the cellular adsorption and penetration of HSV-1 viral particles. Following viral penetration, 51 reduced the expression of HSV-1 IE and L genes and decreased the synthesis of HSV-1 DNA. Furthermore, 51 inhibited the HSV-1induced nuclear factor (NF)-κB activation through blocking the nuclear translocation and DNA binding of NF-κB. The study of Lee et al. [28] gave some insight into the effect of flavonoids, showing the ability of quercetin (19), a "prototype" of flavonoid, to inhibit the expressions of HSV proteins (gD, ICP0) and genes (ICP0, UL13, UL52), and specifically suppress the expression of TLR-3 and inhibit the transcription factors NF-κB and IRF3 [28]. The antiviral activity of halistanol derivatives (96 and 97) against HSV-1 is enabled by the inhibition of viral particles' attachment and penetration; the virucidal effect was also observed. Further analysis showed changes in the levels of proteins ICP27 and the gD of HSV-1. These compounds also act synergistically or with acyclovir [74].

Take-Home Messages
Based on the collected data obtained from the reviewed articles, we may summarize the most promising bioactive natural products that could be used as templates for the further development of anti-HSV drugs through the preparation of analogs using chemical modification processes such as total or semi-synthesis along with combinatorial synthesis, especially with nanoparticles (Table 7). It should be emphasized that we selected bioactive natural products based on the mechanisms of action or types of inhibition induced (against the replication of HSV and its associated steps, or the enzymes involved in the HSV replication cycle). Additionally, these compounds were also selected based on their structure-activity relationship (SAR) that indicates functional groups, which are accountable for the enhanced anti-HSV activity. Based on the above-mentioned selection criteria, where the mechanisms of action, types of inhibition, and SAR are highlighted, we might aid medicinal chemists

Take-Home Messages
Based on the collected data obtained from the reviewed articles, we may summarize the most promising bioactive natural products that could be used as templates for the further development of anti-HSV drugs through the preparation of analogs using chemical modification processes such as total or semi-synthesis along with combinatorial synthesis, especially with nanoparticles (Table 7). It should be emphasized that we selected bioactive natural products based on the mechanisms of action or types of inhibition induced (against the replication of HSV and its associated steps, or the enzymes involved in the HSV replication cycle). Additionally, these compounds were also selected based on their structure-activity relationship (SAR) that indicates functional groups, which are accountable for the enhanced anti-HSV activity. Based on the above-mentioned selection criteria, where the mechanisms of action, types of inhibition, and SAR are highlighted, we might aid medicinal chemists in the design and synthesis of novel and potent compounds useful for the development of anti-HSV drugs. Inhibition of the expressions of HSV proteins (gD, ICP0) and genes (ICP0, UL13, UL52). Additionally, this molecule suppressed the expression of TLR-3 and inhibited the transcriptional factors NF-κB and IRF3. Inhibition of HSV-1 and HSV-2 replication (in vitro) and inactivation of HSV-1 DNA polymerase and HSV-2 protease (proposed as competitive inhibitors via in silico assay).
Hydroxyl, carbonyl, and methyl groups along with phenyl ring (proposed as functional groups via in silico assays).
Alkyl derivatives of gallic acid Octyl gallate (39) Inhibition of multiplication of HSV-1 and suppression of formation of virus progeny at early stages (within 6 h post-infection) in the infected cells.
Hydroxyl, carbonyl, and methyl groups along with phenyl ring (proposed as functional groups via in silico assays).

Stilbene derivative Kuwanon X (51)
Anti-HSV activity through multiple modes of action (impeded cellular adsorption and penetration of HSV-1 viral particles). After viral penetration, this agent decreased the expression of HSV-1 IE and L genes and diminished the synthesis of HSV-1 DNA. Moreover, this molecule prevented the HSV-1-induced nuclear factor (NF)-κB activation via obstructing the nuclear translocation and DNA binding of NF-κB. Hydroxyl and methyl groups (proposed as functional groups via in silico assay).

Steroids
Halistanol sulfate (96) and halistanol sulfate C (97) Suppression of HSV-1 attachment and penetration into the host cells. These substances also impair the levels of ICP27 and gD proteins of HSV-1.
Sulfate groups (assessed as functional groups).

Triterpene glycoside Glycyrrhizic acid (98)
The compound was detected to be an effective inducer of the autophagy activator Beclin 1, which creates a resistance to HSV-1 replication.
Carboxyl and hydroxyl groups along with sugar moiety (assessed as functional groups).
Methoxy and carboxy groups at C-20 were noted to be responsible for the enhanced inhibitory activity against HSV-1 replication.

Pentacyclic triterpenoid
Oleanolic acid (103) Inhibition of HSV-1 and HSV-2 multiplication at the early stage. Suppression of viral gene expression and reduction of viral protein accumulation within infected cells.

Polysaccharides and sulfated polysaccharides
Multiple mechanisms of action (inhibition of HSV replication, inhibition of virus adsorption, suppression of gene expression, suppression of HSV attachment and penetration into the host cell).
Sugar moieties and sulfate groups.

Cyclic peptide Subtilosin
This antiherpetic agent alters the late stages of the viral replicative cycle such as viral glycoprotein intracellular transport.

Concluding Remarks and Future Insights
Currently, there are no effective licensed vaccines available for the treatment of herpesviruses infections, and financial support for their development is running short. Studies on novel anti-HSV activities remain a crucial area in drug discovery, since the currently used medications have failed to induce an effective treatment due to the establishment of drug resistance, and there are still a lot of challenges to developing new antiherpetic drug candidates. Therefore, there is an urgent demand to search for new sources that provide less resistance and reduce unwanted effects. Natural products, as a vast source of biologically active molecules, have proven to induce promising inhibitory activities against HSV infection, and hence, in this paper, we highlighted and summarized exclusively the recent investigations on the most promising compounds derived from various natural origins that can be used as promising and effective antivirals for the treatment of diseases caused by HSV; these are in vitro and in vivo studies based on several assay systems. Additionally, the data depicted in this paper demonstrate a notable impact of structural variations, as well as the analysis of proposed structure-activity relationships, and disclosed that the inhibitory activity profile of natural-derived molecules relies upon the position and nature of their substituents. Despite relatively few isolated antiherpetic agents from natural sources advancing to become clinically successful drugs, these unique compounds could be applied as models for the preparation of analogs using chemical modification procedures such as total or combinatorial synthesis, or the alteration of biosynthetic pathways. More research in this field is greatly needed to achieve the design and optimization of potent and selective antiherpetic drugs with promising levels of activity, reduced adverse effects, low toxicity, and enhanced stability. It is known that clinically used antiherpetic drugs do not heal the disease while modifying the clinical course of the infection by suppressing viral replication and subsequent epithelial damage. Thus, there is an imperative need for comprehensive management of HSV infections based on the obstruction of transmission, suppression of recurrence, viral shedding and complications, and modification of clinical, and promotion of treatment, courses. Moreover, the use of natural products with an accepted level of activity against HSV in combination with synthetic nucleoside analogs (as a combinatory treatment) is another valuable option for the therapy of HSV infection; however, these studies are still limited or have yet to be validated. Therefore, all levels of research, including basic-, clinical-, and population-levels, require continued financial support to promote the development and implementation of effective natural anti-HSV drugs with proper pharmacokinetics, pharmacodynamics, hydrolytic stability, and free toxicological profiles (all these assessments should be taken into consideration with all administered forms of the evaluated drug). Funding: This work received no external funding.

Conflicts of Interest:
The authors declare no conflict of interest.