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.
Highlights
The infectious disease caused by herpes simplex virus has been known since ancient Greek times [1]
Given the importance of Psoromic acid (PA) in exhibiting a notable inhibitory potency against the replication of herpes simplex virus type 1 (HSV-1), it is imperative to study its action against HSV-1 DNA polymerase, a primary enzyme required for the viral replication cycle
The present findings indicated that PA exerted remarkable antiherpetic activities against HSV-1 and herpes simplex virus type 2 (HSV-2)
Summary
The infectious disease caused by herpes simplex virus has been known since ancient Greek times [1]. The standard treatment regimen for HSV relies on the use of acyclovir (ACV) and related nucleoside analogs that target HSV DNA polymerases. PA was subjected to a radiolabeled nucleotide-based assay to explore its anti-enzymatic activity against HSV-1 DNA polymerase and unveil the mechanism underlying its inhibitory effect on HSV-1 replication by targeting such an enzyme. Molecular docking analyses were conducted to further confirm the outcomes of in vitro results and to reveal the binding modes along with the molecular interactions of PA with the active sites of HSV-1 DNA polymerase and HSV-2 protease, which in turn authenticated the inactivation properties of PA towards both enzymes
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