Traditional Chinese Medicine as a Potential Source for HSV-1 Therapy by Acting on Virus or the Susceptibility of Host

Abstract

Herpes simplex virus type 1 (HSV-1) is the most common virus, with an estimated infection rate of 60⁻95% among the adult population. Once infected, HSV-1 can remain latent in the host for a lifetime and be reactivated in patients with a compromised immune system. Reactivation of latent HSV-1 can also be achieved by other stimuli. Though acyclovir (ACV) is a classic drug for HSV-1 infection, ACV-resistant strains have been found in immune-compromised patients and drug toxicity has also been commonly reported. Therefore, there is an urge to search for new anti-HSV-1 agents. Natural products with potential anti-HSV-1 activity have the advantages of minimal side effects, reduced toxicity, and they exert their effect by various mechanisms. This paper will not only provide a reference for the safe dose of these agents if they are to be used in humans, referring to the interrelated data obtained from in vitro experiments, but also introduce the main pharmacodynamic mechanisms of traditional Chinese medicine (TCM) against HSV-1. Taken together, TCM functions as a potential source for HSV-1 therapy by direct (blocking viral attachment/absorption/penetration/replication) or indirect (reducing the susceptibility to HSV-1 or regulating autophagy) antiviral activities. The potential of these active components in the development of anti-HSV-1 drugs will also be described.

Keywords: acyclovir; extracts; herpes simplex virus type 1; natural products; susceptibility; traditional Chinese medicine; traditional herbal medicine.

Figure 1

Molecular structure of related compounds. Bold numbers in parentheses refer to the numbers of corresponding compounds.

Figure 2

Pharmacodynamic mechanism of TCM against HSV-1. Anti-HSV-1 effects of TCM are mainly concentrated on the following three aspects: (i) TCM counteracts HSV-1 by regulating autophagy. mTOR (mammalian target of rapamycin) functions as a negative autophagy regulator. LFE can induce autophagy via decreasing the phosphorylation of mTOR and p70S6K (ribosomal p70S6 kinase). Consequently, Beclin-1 and LC3 (microtubule-associated protein 1 light chain 3)-II are activated, leading to autophagy-mediated clearance of HSV-1 [32]; (ii) TCM exerts anti-viral effects by enhancing immunity. For instance, as ingredients in the HCWEs, quercetin (1) and isoquercitrin (2) inhibit NF-κB (nuclear factor-kappa B) activation [42]. Dpo (32) also improves the organism’s immunity against HSV-1 in a STING-dependent manner, hence contributing to a sustained and significant increase in IRF7 (interferon regulatory factor 7) [59]. Similarly, APS (33) (astragalus polysaccharide) promots immunological function by markedly increasing the expression of TNF-α (tumor necrosis factor-α), IL-6 (interleukin-6), TLR3 (toll-like receptor 3), and NF-κB provoked by HSV-1 [60]. From another perspective, IRF3 (interferon regulatory factor 3) can also be phosphorylated, and phosphorylated IRF3 activated type I interferon expression by binding to ISRE (interferon-stimulated response element) [76]. However, after autophagy-dependent STING delivery of TBK1 (TANK-binding kinase 1) to endosomal/lysosomal compartments, provoked ULK1 (unc-51 like autophagy activating kinase 1) can subsequently inhibit STING (Stimulator of Interferon Genes) function by phosphorylation S366, and IRF3 function is suppressed, thus preventing the persistent transcription of innate immune genes [77]. Mitochondria, the main organelles in eukaryotic cells, play an important role in antiviral process partially due to the mitochondrial localiazation of MAVS (Mitochondrial antiviral-signaling protein). Interestingly, the NEMO (the regulatory subunit of the IKK complex) dependent cGAS-MAVS-TBK1 signaling pathway is essential for IRF3 and NF-κB activation [78]; and (iii) TCM exerts antiviral effects by inhibiting HSV-1 replication or inactivation of HSV-1 in the process of viral attachment/absorption/penetration. HCWEs and quercetin (1) inhibit the infection of HSV-1 via blocking of viral binding and penetration. Additionally, HCWEs, Norcepharadione B (3), and curcumin (35) can inhibit viral replication [42,45,75]. Notoginsenoside ST-4 (21) prevents HSV-1 from penetrating into cells and effectively blocks the synthesis of vp5 [53]. NN-B-5 interrupts the formation of αTIF/C1/Oct-1/GARAT multiprotein/DNA complexes, resulting in reduced expression of ICP0 (infected cell polypeptide 0) and ICP4 [35]. HSV-1, which can escape from various antiviral pathways, can cascade linearly and express immediate early (IE), early (E), and late (L) genes. After expression of the L gene, the cells produce a large number of mature viral particles, causing the cells to rupture and die. Bold numbers in parentheses refer to the numbers of corresponding compounds.