Psoromic Acid, a Lichen-Derived Molecule, Inhibits the Replication of HSV-1 and HSV-2, and Inactivates HSV-1 DNA Polymerase: Shedding Light on Antiherpetic Properties

Abstract

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.

Breaking Down the Barriers to a Natural Antiviral Agent: Antiviral Activity and Molecular Docking of Erythrina speciosa Extract, Fractions, and the Major Compound

“…To investigate the molecular interaction pattern by which vitexin might exert its antiviral activity, the molecular docking approach was employed. Several molecular targets commonly used for screening small molecules in the field of antiviral drug discovery such as HSV type‐1 DNA polymerase, HSV type‐1 thymidine kinase, HAV 3C proteinase, HBV capsid protein, and HCV protease‐helicase, were exploited for in silico study. A prerequisite to any successful experiment is the validation step.…”

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

“…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]. In another study, psoromic acid (45), a bioactive, lichen-derived molecule, was tested for its inhibitory action against HSV-1 and HSV-2 [46]. The results advocated that this molecule effectively inhibited HSV-1 (IC50 = 1.9 μM; SI: 163.2) and HSV-2 (EC50 = 2.7 μM; SI: 114.8) replication compared with that of ACV (for HSV-1 IC50 = 2.6 μM; SI: 119.2 and for HSV-2 EC50 = 2.8 μM; SI: 110.7).…”

“…In an in vitro assay, 45 was proved to be a nonnucleoside inhibitor as well as a competitive inhibitor of the HSV-1 DNA polymerase with respect to dTTP incorporation (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). In another study, psoromic acid (45), a bioactive, lichen-derived molecule, was tested for its inhibitory action against HSV-1 and HSV-2 [46]. The results advocated that this molecule effectively inhibited HSV-1 (IC 50 = 1.9 µM; SI: 163.2) and HSV-2 (EC 50 = 2.7 µM; SI: 114.8) replication compared with that of ACV (for HSV-1 IC 50 = 2.6 µM; SI: 119.2 and for HSV-2 EC 50 = 2.8 µM; SI: 110.7).…”

Brassicasterol with Dual Anti-Infective Properties against HSV-1 and Mycobacterium tuberculosis, and Cardiovascular Protective Effect: Nonclinical In Vitro and In Silico Assessments

“…Targeting viral and cellular enzymes that perform significant functions during the HSV-1 replication cycle could help the development of effective broad-spectrum antiherpetic drugs. For instance, HSV-1 DNA polymerase was reported to be an essential enzyme required for viral replication [3], while HSV-1 TK is an important enzyme that catalyzes the transfer of the gammaphospho group of ATP to thymidine to generate dTMP in the salvage pathway of pyrimidine synthesis, and hence the dTMP serves as a substrate for DNA polymerase during viral DNA replication [36]. Targeting viral and cellular enzymes that perform significant functions during the HSV-1 replication cycle could help the development of effective broad-spectrum antiherpetic drugs.…”

“…Most HSV-1 infections are acquired during childhood, and infection is lifelong. Infections with HSV-1 are typically oral herpes but HSV-1 can also be transmitted to the genitals and causes genital herpes [3][4][5]. Oral herpes infection is commonly asymptomatic, however, in immunocompromised patients with advanced HIV infection, HSV-1 could generate obvious and severe symptoms with regular recurrences [6].…”