Anti-HSV-1 agents: an update

Abstract

Herpes simplex virus type I (HSV-1) is a member of the α-herpesvirus subfamily and is capable of causing herpes simplex keratitis, herpes labialis, and herpes simplex encephalitis. HSV-1 is well known for its lytic infections at the primary sites and for establishing latency in the sensory neuronal ganglia, with occasional recurrent infections. To date, there are no approved commercially available vaccines, and anti-HSV-1 drugs such as specific or non-specific nucleotide (nucleoside) analogs and helicase-primase inhibitors have become the main clinical agents for the treatment of HSV-1 infections despite challenges from resistance. Therefore, development of new anti-HSV-1 compounds or therapies is key to addressing the issue of resistance. The present review provides an update on the progress made over approximately 60 years regarding anti-HSV-1 agents while also highlighting future perspectives for controlling HSV-1 infections.

Keywords: HSV-1; agents; antiviral; herpes virus; immunomodulation.

FIGURE 1

Anti-HSV-1 agents exert their antiviral effects by targeting the viral lifecycle. HSV-1 infects host cells through a chain of roughly five processes: binding, fusion, replication, assembly, and release. Most of the active substances play inhibitory roles during the cell binding and viral DNA replication stages.

FIGURE 2

Anti-HSV-1 agents exert their antiviral effects by regulating the host signaling pathways. Following HSV-1 infection, the active substances exert inhibitory effects through various signaling pathways. The HSV-1 DNA uses the toll-like receptor-3 (TLR3) to stimulate cells to produce the transcription factors interferon regulatory factor 3 (IRF3) or nuclear factor kappa-B (NF-κB), which then induce expressions of the type I interferon and pro-inflammatory cytokine genes. Cyclic GMP-AMP synthase (cGAS) can sense the damaged DNA and activate the stimulator of interferon gene (STING), which then activates TANK-binding kinase 1 (TBK1) and eventually activates IRF3 or NF-κB to play autoimmune roles. It can mediate pyrodeath and IL-1β secretion by influencing the formation of NLRP3 inflammasomes. Signal transducer and activator of transcription 3 (STAT3), which is inhibited by the upstream suppressor of cytokine signaling 1 (SOCS1), can regulate cellular activities like cell growth and immune responses. Ras-protein-specific guanine nucleotide-releasing factor 2 (Ras-GRF2) activates c-Raf to regulate the signaling of extracellular regulated protein kinases (ERK1/2), while ERK inhibition promotes viral replication.