Recent Advances in Antiviral Activities of Triterpenoids

Triterpenoids, important secondary plant metabolites made up of six isoprene units, are found widely in higher plants and are studied for their structural variety and wide range of bioactivities, including antiviral, antioxidant, anticancer, and anti-inflammatory properties. Numerous studies have demonstrated that different triterpenoids have the potential to behave as potential antiviral agents. The antiviral activities of triterpenoids and their derivatives are summarized in this review, with examples of oleanane, ursane, lupane, dammarane, lanostane, and cycloartane triterpenoids. We concentrated on the tetracyclic and pentacyclic triterpenoids in particular. Furthermore, the particular viral types and possible methods, such as anti-human immunodeficiency virus (HIV), anti-influenza virus, and anti-hepatitis virus, are presented in this article. This review gives an overview and a discussion of triterpenoids as potential antiviral agents.


Introduction
Viral infections are currently the main infectious disease worldwide [1], accounting for more than two thirds of infectious diseases [2]. Viruses that invade the human body can be divided into two categories. One is a group of viruses that are long-term parasites in the human body, including chickenpox, rubella, herpes, measles, smallpox, polio, Japanese encephalitis, mumps, cytomegalovirus (CMV), hepatitis B/C virus (HBV/HCV), dengue virus (DENV), human influenza virus, human immunodeficiency virus (HIV), and human papilloma virus (HPV). The other group consists of viruses that are long-term parasites in animals such as chickens, dogs, pigs, horses, and sheep, which are close to humans. These viruses, which can also infect humans across species, include avian influenza virus, rabies virus, hantavirus, and other viruses [3].
Viruses usually spread from one region to another, and in the past 10 years, the largescale outbreaks of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), Ebola, and other viruses have caused considerable threats to human health. Moreover, the residual effects of viral infections cause considerable deleterious effects, pain, and inconvenience to patients. For example, the "cytokine storm" triggered by influenza virus infection can cause lung inflammation and acute respiratory distress syndrome, which is an important cause of mortality [4,5]. The neurotoxicity induced by herpes zoster virus infection often causes ganglion inflammation and necrosis. After invading the sensory nerve endings of the skin, this virus can move along the nerve to the ganglion of the posterior root of the spinal cord, where it remains latent.
Presently, vaccines and screening antiviral drugs are the main drugs used for the prevention and treatment of human viral infections [6]. However, it is difficult to develop an effective vaccine, and the side effects are unpredictable, such as the blood clots that can occur following the administration of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine [7]. In addition, vaccination is not effective in 100% of patients, and there is a chance that someone who is vaccinated against the coronavirus could still catch it [8]. Moreover, many viruses are zoonotic, and vaccines against human viral disease cannot eradicate animal-derived viruses. Presently, the focus of antiviral drug research is limited to several types of viruses, such as HIV, herpes, influenza, hepatitis, and respiratory viruses [9].
Triterpenoids are important plant metabolites characterized by six isoprene (2-methyl-1,3-butadiene, C 5 H 8 ) units. Studies reported that triterpenoids have a wide range of pharmacological effects and important biological activities, especially anti-inflammatory, hypoglycemic, antitumor, and antiviral activities [10]. Triterpenoids have been proven to be important in the defense mechanisms of plants against pathogenic infection. Recently, an increasing number of studies have shown that triterpenoids exhibit excellent antiviral activities [11]. These compounds can prevent viral adsorption and invasion into host cells in the early stage and thereby inhibit the viral replication process after cell infection.
This review summarizes the antiviral activity of triterpenoids and the mechanism underlying these effects and mainly focuses on their mechanism of action against HIV, influenza virus, HBV, HCV, and coronavirus (CoVs) (Figure 1). This review provides important evidence to support the design and development of triterpenoids as antiviral drugs.

Structure and Classification of Triterpenoids
According to the number of isoprene units in the molecule, terpenoids can be divided into groups such as monoterpenes, sesquiterpenes, diterpenes, triterpenes, tetraterpenes, and polyterpenes. Among these groups, the tetracyclic triterpenes and pentacyclic triterpenes are the most common. Triterpenoids exist widely in nature in the free form or as glycosides or esters combined with sugars. There are numerous modifications of the carbon skeleton of triterpenoids, which is a complex and diverse structure that imparts a variety of functions to these compounds, making them the focus of considerable interest. Triterpenes are a major class of chemical compounds found in natural plants and can be categorized into acyclic, monocyclic, tricyclic, tetracyclic, and pentacyclic triterpenoids [10]. Among them, tetracyclic and pentacyclic triterpenoids have been the focus of more extensive attention than the other classes. Tetracyclic triterpenoids can be divided into dammarane, lanostane, tirucallane, cycloartane, cucurbitanes, and meliacane types. Pentacyclic triterpenoids can be divided into oleanane, ursane, lupine, and friedelane types [12].   Smith. Compound 43 showed anti-HIV activity with a half-maximal effective concentration (EC 50 ) of 20.69 µg/mL and a selectivity index > 6.62 [31]. A trinorcycloartane triterpenoid, lancifodilactone H (44); an A-ring-secocycloartane triterpenoid, lancifoic acid A (45); and nigranoic acid (46) isolated from S. lancifolia can inhibit HIV, with EC 50 values of 16.6, 16.2, and 10.3 µg/mL, respectively ( Figure 2) [32]. The triterpenoid angustific acid A (48) (Figure 2), isolated from Kadsura angustifolia, exhibited inhibitory activity against HIV, with an EC 50 value of 6.1 µg/mL and a therapeutic index (TI) > 32.8 [33]. The triterpenoid lancilactone C (50) (Figure 2), isolated from Kadsura lancilimba, showed inhibitory effects on the replication of HIV, with an EC 50 value of 1.4 µg/mL and a TI of greater than 71.4 [34]. The cycloartane triterpenoids nigranoic acid (46) and kadsuranic acid A (47), isolated from Kadsura heteroclita, have significant inhibitory effects on HIV-1 PR, with IC 50 values of 15.79 and 20.44 µM, respectively ( Figure 2) [35].
Oleanolic acid (OA, 8), betulinic acid (BA, 16), betulin (17), and lupeol (18) are representative pentacyclic triterpenoids that are widely found in nature with a broad antiviral spectrum ( Figure 2). Lupeol (18), extracted from Hemidesmus indicus R. Br., has an inhibitory effect on HIV-1 RT-related ribonuclease, with an IC 50 of 11.6 µM [36]. BA (16) is a naturally occurring pentacyclic lupane-type triterpenoid that is usually isolated from birch trees, and it has potent anti-HIV activity (EC 50 and IC 50 of 1.4 µM and 13 µM, respectively) [37]. What differentiates these compounds from traditional anti-HIV drugs is that the acylated derivatives at position C-3 of BA (16) inhibit HIV maturation, and the amidated derivatives at position C-28 prevent HIV from integrating into cell membranes [38], as shown in Figure 5 [24]. Bifunctional BA (16) derivatives are the series of compounds obtained by modifying positions C-3 and C-28 at the same time. The strongest anti-HIV effect is observed in ([[N-[3beta-O-(3 ,3 -dimethylsuccinyl)-lup-20(29)-en-28-oyl]-7-aminoheptyl]carbamoyl] methane), with an EC 50 value of 0.0026 µM [39]. BA (16) and its derivatives with modifications at both C3-OH and C17-COOH can block virus fusion and virus maturation simultaneously as bifunctional inhibitors [40]. The isopropenyl group at position C-19 may not be an active pharmacophore, but proper modification can improve the water solubility of the drug, and thereby improving the pharmacokinetic properties of the drug. 2. R 1 as a hydrogen bond donor is unfavorable to the activity. 3. Changing the C-30 allyl group has no obvious effect on drug activity. C: 1. C-3 acylation can inhibit HIV maturation and C-28 amidation can prevent HIV from integrating into cell membranes. 2. The atomic length of the side chain at position C-28 is extremely significant for improving the antiviral efficacy, and the side chain structure containing amide groups is very important for activity. 3. The free hydroxyl group of R 3 and the free carboxyl group at the end of R 2 are necessary for anti-HIV activity. 4. When X is a secondary amine ring such as piperidine, it can significantly improve metabolic stability.

Anti-Influenza Virus
The influenza virus is the respiratory virus posing the greatest threat to human health, and it causes millions of people to have upper respiratory tract infections yearly. The high mutation rate of influenza viruses and the recombination between viruses makes it difficult for anti-influenza drugs to effectively treat infections caused by the changing influenza viruses. Currently, the effectiveness of the two types of chemical drugs, M2 ion channel blockers and neuraminidase inhibitors, for the treatment and prevention of influenza viruses is limited by severe drug resistance. Although vaccines are the key drugs for the prevention and treatment of viral infections in humans, some viruses such as CoV are zoonotic, and vaccines against humans cannot be used to eradicate them. In addition, the extremely high gene reconfiguration efficiency of influenza viruses makes them effective targets for vaccines.
Triterpenes have also shown obvious effects against the influenza virus, such as ursolic acid and betulinic acid derivatives, which exhibit significant anti-influenza-virus activity ( Table 2) [40]. GL (1) inhibits the replication of the human parainfluenza virus type 2 (HPIV2) by inhibiting the synthesis of genomic RNA, mRNA, and protein [55]. Furthermore, the combination of GL (1) and ribavirin effectively treated H1N1 influenza virus infection in vivo and inhibited the production of pro-inflammatory cytokines IL-6, tumor necrosis factor (TNF)-α, and IL-1β induced by viral infection, indicating that GL (1) reduced inflammation and inhibited the viral infection [56].
The structural modification of UA (10) produced a compound that prevented the H5N1 influenza virus from penetrating host cells [59]. The esterification of the C-17 carboxyl group of UA (10) significantly increased the antiviral activity, whereas the conversion of the carboxyl group into an amide increased the antiviral activity and reduced the cytotoxicity.
Diammonium glycyrrhizin (DG, 4) ( Figure 2) is a salt form of glycyrrhizinate, a major active component of licorice root extract, with various pharmacological activities that is widely used as an anti-inflammatory. DG (4) has antiviral effects, reduces inflammation induced by viral infections, exhibits anti-H1N1 activity [60], and significantly reduces the virus titer and nucleoprotein expression of H1N1-infected MDCK cells. Furthermore, DG (4) does not directly inactivate the H1N1 virus or act on the adsorption and penetration of the virus, but it upregulates the expression of the interferon-γ (IFN-γ) gene in H1N1-infected cells. Moreover, DG (4) downregulated the expression of the TNF-α gene, reducing the inflammatory response induced by H1N1 and the immune damage to host cells. G-Rb1 (29) interacts with viral hemagglutinin (HA) protein to prevent viral adhesion to the α2-3 sialic acid receptor on the surface of the host cell and thereby interferes with the adhesion process of the virus [61].
The compound CYY1-11, which was selected from a mini-library of pentacyclic triterpene-cyclodextrin conjugates, is a hexavalent BA (16) derivative with good activity against the H1N1 influenza virus, with an IC 50 of 5.2 µM. CYY1-11 directly targets the influenza HA protein, inhibiting viral replication and preventing viral particles from adsorbing and infecting host cell receptors [62]. Paracaseolin A (24) (Figure 2) is a triterpenoid paracaseolin isolated from Sonneratia paracaseolaris that shows a significant anti-H1N1-virus effect, with an IC 50 of 28.4 µg/mL [63].

Anti-CoV
Since the beginning of the 21st century, outbreaks of CoV have caused fatal pneumonia in humans. CoV is a large family of viruses, and in only two decades, three strains have crossed species barriers, rapidly emerging as human pathogens that have resulted in life-threatening diseases with pandemic potential, such as SARS-CoV, MERS-CoV, and SARS-CoV-2 [64]. SARS-CoV and MERS-CoV are zoonotic viruses derived from bats and dromedaries [65], and the outbreak of SARS-CoV-2 at the end of 2019 caused considerable human mortality and large-scale sustained illness [66]. SARS-CoV-2 is considered a respiratory disease, but studies have shown that the virus affects multiple organs, including the central nervous system [67]. The high incidence of CoVs poses a serious threat to human health and creates considerable challenges to human life.
GL (1) inhibits SARS-CoV replication, adsorption, and penetration, with a better antiviral activity than that of ribavirin and an SI of 67 [68]. In a previous study, GL (1) was found to be most effective when administered both during and after the adsorption period. Furthermore, GL (1) induced NOS production in Vero cells and inhibited viral replication when a nitrous oxide donor (DETA NONOate) was added to the culture medium [68].
Studies testing the activity of 15 GL (1) derivatives found that the introduction of 2-acetamido-beta-d-glucopyranosylamine into the glycoside chain of GL (1) increased the anti-SARS-CoV activity by 10-fold compared to that of the parent GL (1) [69]. Amides and conjugates of GL (1) with two amino acid residues and a free 30-COOH function were found to exhibit up to 70-fold increased activity against SARS-CoV compared to the parent compounds; however, the accompanied increased cytotoxicity decreased the selectivity index [69].
GL (1) can be used for the treatment and prevention of SARS-CoV-2 [70], and there are numerous possible mechanisms mediating its activity against viruses, including increased NO production in macrophages, the regulation of transcription factors and cellular signaling pathways, the direct alteration of the viral lipid bilayer membrane, and binding to the angiotensin-converting enzyme 2 (ACE2) receptor [70][71][72]. Furthermore, GL (1) inhibited the protease M of SARS-CoV-2, which can process polyproteins, the translation products of viral RNA, which are attractive drug targets (Table 3) [73].
Some active compounds such as GL (1) strongly bind to part of the amino acid residue of protease M, which can inhibit the enzymes, and they have good solubility, absorption, and permeability and are nontoxic, and noncarcinogenic. Magnesium isoglycyrrhizinate (MgIG, 7) (Figure 2), a magnesium salt of the 18-α glycyrrhizic acid stereoisomer, has been identified as a potential adjuvant treatment for SARS-CoV-2 (Table 3) [74]. OA (8), which also exerts anti-SARS-CoV-2 activity [75], is a 3CL hydrolase inhibitor of this virus, and the binding energy consumed by 3CL hydrolase is similar to that of radcivir but lower than that of ritonavir. Studies have shown that maslinic acids (MA, 51), UA (10), BA (16), and betulin (17) (Table 3).

Anti-Hepatitis Virus
Viral hepatitis can be caused by a variety of hepatitis viruses, which are usually divided into A, B, C, D, and E types. The A and E forms of the virus cause acute infections and can be transmitted through the fecal-oral route. The B, C, and D viruses mainly cause chronic infections, which are transmitted through blood and body fluids. Recently, traditional Chinese medicine (TCM) practices and formulations have been widely explored for the treatment of viral hepatitis and, in particular, the pentacyclic triterpenes have been a focus.

Anti-Hepatitis A Virus (HAV)
The hepatitis A virus (HAV), which is the main cause of hepatitis A, is a food-borne disease, and vaccination is the most effective preventative treatment. Early research has shown that GL (1) achieved a concentration-dependent inhibition of the replication of HAV in PLC/PRF/5 cells (Table 4) [78]. Gi-Rb1 (29) and G-Rg1 (32) have been shown to significantly inhibit HAV in vitro (Table 4) [79].

Anti-HBV
Chronic hepatitis B is a long-term progressive disease caused by HBV infection, which leads to hepatitis, cirrhosis, and even liver cancer. Presently, the main drugs for the treatment of chronic hepatitis B are IFN in combination with nucleoside drugs such as lamivudine, adefovir dipivoxil, and clevudine. The low treatment success rate and severe side effects of IFN and the increased resistance to nucleoside drugs has limited the clinical application of these drugs [80]. Triterpenoids have been proven to have obvious advantages in the treatment of viral diseases (Table 5).
A study showed that lamivudine in combination with GL (1) effectively controlled HBV replication in chronic HBV carriers [81]. is an effective component of the TCM formulation Astragalus membranaceus. AS-IV (49) showed a good anti-HBV effect by inhibiting the cell proliferation or viral DNA replication of infected cells [84]. G-Rg3 (31) inhibits DNA replication and viral protein formation [85], and G-Rg1 (32) enhanced the immunoactivity of an anti-HBsAg vaccine, thereby promoting the secretion of IgG2b and IFN-γ by Th1 cells in mice and the secretion of IgG1 and IL-4 from Th2 cells to exert an anti-HBV effect [86].

Anti-HCV
HCV infection usually causes chronic hepatitis C (CHC), liver cirrhosis, and liver cancer, and approximately 185 million people are infected with the HCV. During the HCV replication process, NS3/4A serine protease mediates the cleavage of polyprotein precursors, which promotes the maturation and function of nonstructural proteins. Clinically, >95% of CHC patients are treated with antiviral drugs that act against NS3/4A protease, which can induce a sustained virological response. However, some patients with liver cirrhosis still develop hepatocellular carcinoma, and there is serious drug resistance to these agents, which have multiple side effects. Triterpenoids have been proven to have obvious advantages in the treatment of HCV ( Table 6).
The active ingredient, OA (8), was isolated from Dipsacus asperoides and exhibited a good anti-HCV activity [87]. The structure-activity relationships of OA (8) against HCV are shown in Figure 7. [24]. EA (9), which is the derivative of OA (8), also showed activity against HCV, and the mechanism of action may be related to inhibiting the binding of the HCV envelope protein E2 to the host cell CD81 receptor, which prevents HCV from recognizing the host. The A and B loops and the left side structures of the C and E loops of EA (9) are highly conserved, and consequently its modification has an adverse effect on the antiviral activity, whereas a reasonable modification of the D loop improves antiviral activity [24]. To improve the water solubility of OA (8) and EA (9), they were coupled with β-CD to obtain a series of new triazole-bridged α-CD-pentacyclic triterpenoids. Studies have shown that the new conjugate has reduced hydrophobicity and no cytotoxicity or hemolytic activity [88]. 3-R1 in the β configuration is better than α configuration. 2. A free carboxyl group at the end of R1 is better than a free amino group. B: The R2 hydroxyl group is better than a methoxy group, and has the potential to inhibit HCV protease.
The NS5b gene plays a key role in the synthesis and replication of viral RNA, catalyzing the synthesis of negative RNA strands using HCV genomes as templates and the synthesis of negative RNA strands with HCV genomes as templates [89]. OA (8) and UA (10) competitively inhibit the activities of NS5B and RNA polymerase, and the IC 50 values of OA (8) and UA (10) were about 1.8 µM and 6.8 µM, respectively [89]. HCV infection can cause changes in mitochondrial dynamics and weaken the immunity. G-Rg3 (31) inhibited the proliferation of HCV-infected cells by affecting their expression of p21, repairing abnormal mitochondrial division, and inhibiting persistent HCV infection [90].

Anti-Rotavirus (RV)
RV is the main cause of severe enteritis in children under 5 years old, and it mainly infects the intestinal mucosa cells and induces enterotoxins, leading to malnutrition and even death in children. There is currently no clinical treatment for RV infection. 2α-Hydroxyursolic acid (12) (Figure 2) extracted from guava leaves has a strong anti-humanrotavirus (HRV) effect in vitro, which stimulates the secretion of IFN-γ, enhancing immune function (Table 7) [91]. UA (10) was also reported to inhibit the replication of RV and affect the maturation of viral particles (Table 7) [92]. Moreover, G-Rb2 (30) and 20(S)-GRg3 (31) exhibited good anti-RV effects as immunomodulators (Table 7) [93].

Anti-Herpesvirus
Herpesviruses are double-stranded DNA viruses with icosahedral symmetry, belonging to the Herpesviridae family. Most herpes viruses can cause human infections, including herpes simplex virus (HSV)-1 and HSV-2, the African lymphocyte Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and human cytomegalovirus (HCMV) [94]. The herpesvirus can infect any organ or tissue in the human body to cause a variety of diseases. Recently, herpesvirus infection has become one of the main causes of death in people with impaired immune function. Presently, there are still no anti-herpesvirus drugs with high efficiency and specificity and without side effects.
Carbenoxolone sodium (CBX, 5) and cicloxolone sodium (CCX, 6) are derivatives of triterpenoid GL (1), found in glycyrrhiza plants, that inhibit HSV-1 and HSV-2 ( Figure 2). These compounds significantly inhibit viral replication and thereby reduce the number of infectious viral particles (Table 8) [95]. Another study showed that GL (1) effectively inhibits the adsorption of HSV to rat brain capillary endothelial cells and polymorphonuclear leukocytes, thereby significantly reducing the inflammatory response caused by the HSV infection of host cells [96]. GL (1) induces antiviral effects through the prevention of the early invasion of host cells by EBV, with an IC 50 of 0.04 mM (Table 8) [97]. GL (1) is a strong beclin 1 activator of autophagy, which inhibits the replication of the virus [98]. Moreover, combining GL (1) with some antiviral and anti-inflammatory enzymes or proteins such as lysozyme (LYS) and lactotransferrin (LAC) produced a synergistic effect [99] against the activity of the HSV-1 virus. Furthermore, the combination can reduce the adverse reactions such as edema, hypokalemia, and hypertension caused by large doses of GL (1). Generally, drugs have little effect on the viral incubation period, but GL (1) inhibits the replication of latent KSHV in B lymphocytes [100]. Furthermore, GL (1) reduces the synthesis of KSHV latency protein, inducing the apoptosis of infected cells, and thereby exerts antiviral effects [101]. 20(S)-GRg3 (31) has a significant inhibitory effect on HSV-1 and HSV-2, with an IC 50 of 35 µM (Table 8) [102].
HCMV is a ubiquitous herpes virus that can latently infect hosts throughout their life cycle and is reactivated when the immune system is weak. Currently, there is no vaccine for HCMV infection and existing antiviral drugs mainly target viral enzymes and have obvious adverse reactions [103]. Therefore, it extremely imperative to find compounds with anti-HCMV properties. OA (8) and UA (10) have anti-guinea pig cytomegalovirus (GPCMV) effects [104,105] with inhibitory rates of 18%, 35%, and 84% on GPCMV adsorption, penetration, and replication, respectively. Furthermore, the antiviral target is the inhibition of virus synthesis.

Anti-DENV
DENV is the most common arboviral disease worldwide, with 100 million symptomatic cases annually [106], and despite its major impact on global human health and the huge economic burden, there is no antiviral drug available to treat the disease [107]. DENV was listed as one of the top 10 global health threats in 2019 by the World Health Organization (WHO) [108]. The first tetravalent DENV vaccine was licensed in 2015 for individuals aged 9 to 45 years; however, most cases are reported in infants and young children. These facts, coupled with the limited efficacy of the vaccine against DENV serotype 2, stress the need to continue the search for compounds with anti-DENV activity.

Anti-Norovirus (NoV)
NoV is the main pathogen causing nonbacterial acute gastroenteritis in humans and acute diarrhea in infants and young children [112]. NoV constitutes a considerable health risk to society and is the cause of >50% of viral gastroenteritis cases worldwide, whereas >85% of nonbacterial gastroenteritis cases are related to NoV [113]. Recently, considerable progress has been achieved in the development of anti-NoV drugs, and discovering compounds with anti-NoV activity from natural products is a laudable strategy. Astragaloside has anti-NoV effects [114] and has been proven to significantly downregulate the levels of TNF-α, IL-1β, and IL-6 while enhancing the anti-inflammatory responses of patients. Furthermore, it enhances the activity of the intestinal immune cells to eliminate viruses by regulating the protein kinase-R (PKR)/p-PKR signal transduction pathway.

Anti-Coxsackievirus (CV)
CV is divided into A and B types, and it is the main pathogen causing viral myocarditis and dilated cardiomyopathy in children and adolescents. The early innate immune response of the host to CV infection depends on IFN, and AS-IV (49) has been shown to upregulate the expression of IFN-γ mRNA, which inhibits CV [115]. GL (1) treatment has a significant effect on viral myocarditis caused by CV [115], and it inhibits the enhanced expression of TNF-α, IL-1β, IL-6, and other inflammatory cytokines caused by CV infection.

Anti-Adenovirus (AdV)
AdV was first isolated in 1949 when a biological sample from an organism with bovine nodular dermatitis disease was inoculated into chicken embryos. In 1953, human AdV (HAdV) was isolated from the tonsils of children. HAdV include seven types and 65 subtypes from A to G, which can cause diseases such as acute upper and lower respiratory tract infections, explosive conjunctivitis, gastroenteritis in infants, and acute hemorrhagic cystitis.
AdV is highly contagious, especially in densely populated places and can be spread through droplets and contact, which leads to regional epidemics or outbreaks. HAdV3 is the main pathogen that causes acute respiratory diseases and pharyngeal conjunctival fever. Currently, there is no effective preventative vaccine, and specific drugs have not yet been discovered or developed. AS-IV (49) has anti-AdV activity in vitro [116] and damages the self-assembly stage of AdV by a mechanism of action that is related to the inhibition of the expression of hexon protein. In addition, this agent inhibits the replication and adsorption of AdV.

Anti-Enterovirus (EV71)
EV71 is one of the common pathogens responsible for hand, foot, and mouth disease (HFMD) [117]. Children who experience HFMD commonly have myocardial and nervous system damage, which causes systemic complications and seriously endangers the health of children. GL (1) inhibits EV71 infection of host cells and has been shown to have no direct inactivation effect on the EV71 virus but acts after the virus enters the cell to exert its antiviral effect [87]. G-Rb1 (29) exerts antiviral activity against EV71-infected suckling mice [118] and reduced the CPE of RD cells infected by EV71. In addition, G-Rb1 (29) reduces EV71induced viral protein-1 expression both in vivo and in vitro while inducing natural immune responses in the body and enhancing IFN responses [118]. UA (10) showed strong inhibitory activity against EV71, and OA (8), asiatic acid (AA, 14), and synthetic derivatives of GL (1) and OA (8) also showed inhibitory effects (Figure 2). These compounds could be further optimized as candidates for the treatment of EV71 [119]. The triterpenoids lanosta-7, 9 (11), 24-trien-3-one, 15;26-dihydroxy (GLTA, 37), and ganoderic acid Y (GLTB, 38), isolated from G. lucidum, showed anti-EV71 activity (Figure 2) [120]. Furthermore, GLTA (37) and GLTB (38) were proven to block the adsorption of viruses to host cells by interacting with viral particles (Table 10).

Anti-Porcine Reproductive and Respiratory Syndrome Virus (PRRSV)
Porcine reproductive and respiratory syndrome virus (PRRSV) is an enveloped singlestranded positive-stranded RNA virus, which constitutes a considerable threat to pigs. Current existing vaccines cannot provide comprehensive protection against this virus. GL (1) inhibits the cellular penetration of PRRSV and significantly reduces its proliferation and the expression of its encoded protein [121]. Gly-CDs synthesized based on GL (1) inhibit the invasion and replication of PRRSV by stimulating the antiviral innate immune response and inhibiting the accumulation of intracellular reactive oxygen species (ROS) caused by PRRSV infection (Table 11) [122]. Gly-CDs also stimulate cells to regulate the expression of some host restriction factors to inhibit PRRSV proliferation, including DDX53 and NOS3.

Compounds
Targets References

Conclusions and Future Prospective
The rapid mutation of viruses enables them to easily develop resistance to drugs, which limits the use of currently available drugs. Therefore, the development of broad-spectrum antiviral drugs is important, especially for newly emerging viruses, such as SARS-CoV-2. Traditional herbal medicines and plant-based natural compounds are rich resources of new antiviral drugs. Many traditional herbal medicines possess antiviral activities against a plethora of viral strains, exerting their antiviral activities on the virus life cycle, including viral entry, replication, assembly, and release as well as the virus-host-specific interactions, allowing them to theoretically lead to the discovery of broad-spectrum antivirals.
Triterpenoids are the focus of considerable attention because of their novel chemical structure and unique mechanism of action. In recent years, an increasing number of studies have reported on the effects of triterpenoids on viruses. This present article systematically summarizes the recent advances in the study of the types, structural characteristics, and potential antiviral mechanisms of triterpenoids. The investigation of the antiviral mechanisms of these triterpenoids leads to the conclusion that they are mainly exerted through the inactivation of viral particles, the prevention of viral replication and entry into host cells, and the regulation of immunity. The present review aims to provide evidence to support the effectiveness of the strategy of discovering new antiviral drugs from triterpenoids.
However, there are still some obstacles to developing broad-spectrum antiviral drugs from triterpenoid compounds. The targets and mechanisms underpinning some natural products remain unclear, potential side effects have not been fully investigated, and the activities of triterpenoids are usually moderate. Advanced technology for chemical modification, investigations into underlying biological mechanisms, and progress in drug design will facilitate future developments in the field. In addition, the structure of triterpenoids determines that they have high polarity and poor bioavailability, which limits their biofilm permeability and absorption. Therefore, it is necessary to improve the dissolution and absorption ability of triterpenoids by chemical or pharmaceutical methods. For example, the esterification or amidation structure modification of triterpenoids can increase their lipid solubility, membrane permeability, and oral absorption rate. In addition, new pharmaceutical dosage forms and new technologies can also improve the oral bioavailability of triterpenoids, such as oral self-emulsifying systems, liposomes, microspheres, microcapsules, nanomicelles, etc. Furthermore, appropriate administration routes can also improve the bioavailability of triterpenoids, for example, transdermal drug delivery systems, colonic administration, nasal mucosa administration, pulmonary inhalation administration, etc.