Neutral sphingomyelinase-inhibiting guanidines prevent herpes simplex virus-1 replication

Area of Science:

• Biochemistry
• Virology
• Medicinal Chemistry

Background:

• Herpes simplex virus-1 (HSV-1) poses a significant public health challenge.
• Developing novel antiviral agents targeting viral replication mechanisms is crucial.

Purpose of the Study:

• To synthesize and evaluate novel guanidinium derivatives for their inhibitory activity against HSV-1 replication.
• To investigate the correlation between molecular lipophilicity and antiviral efficacy.
• To identify the specific molecular targets of the most potent compounds.

Main Methods:

• Synthesis of a series of guanidinium derivatives with varying lipophilic properties.
• In vitro assessment of inhibitory activity against HSV-1 replication.
• Evaluation of neutral sphingomyelinase (nSMase) and other phospholipase activities.
• Analysis of viral gene expression (ICP-4) and DNA replication.

Main Results:

• Lipophilicity of guanidinium derivatives positively correlated with inhibitory potential against HSV-1.
• Undecylidene-aminoguanidine (C11AG), an 11-carbon derivative, demonstrated potent antiviral activity (EC50 = 2.6 microM) with low cytotoxicity (CC50 = 31 microM).
• C11AG inhibited HSV-1 immediate early gene ICP-4 expression and viral DNA replication, suggesting interference with cellular signaling pathways regulating viral gene expression. It also inhibited nSMase activity.

Conclusions:

• Undecylidene-aminoguanidine (C11AG) is a highly effective inhibitor of HSV-1 replication.
• The antiviral activity of C11AG is linked to its ability to inhibit neutral sphingomyelinase and interfere with viral gene expression.
• C11AG represents a promising lead compound for the development of novel anti-HSV therapies.