Current landscape in antiviral drug development against herpes simplex virus infections

Abstract

Herpes simplex viruses (HSV) are common human pathogens with a combined global seroprevalence of 90% in the adult population. HSV-1 causes orofacial herpes but can cause severe diseases, such as the potentially fatal herpes encephalitis and herpes keratitis, a prevalent cause of infectious blindness. The hallmark of HSV is lifelong latent infections and viral reactivations, leading to recurrent lesions or asymptomatic shedding. HSV-1 and HSV-2 can cause recurrent, painful, and socially limiting genital lesions, which predispose to human immunodeficiency virus infections, and can lead to neonatal herpes infections, a life-threatening condition for the newborn. Despite massive efforts, there is no vaccine against HSV, as both viruses share the capability to evade the antiviral defenses of human and to establish lifelong latency. Recurrent and primary HSV infections are treated with nucleoside analogs, but the treatments do not completely eliminate viral shedding and transmission. Drug-resistant HSV strains can emerge in relation to long-term prophylactic treatment. Such strains are likely to be resistant to other chemotherapies, justifying the development of novel antiviral treatments. The importance of developing new therapies against HSV has been recognized by the World Health Organization. In this review, we discuss the current approaches for developing novel antiviral therapies against HSV, such as small molecule inhibitors, biopharmaceuticals, natural products, gene editing, and oligonucleotide-based therapies. These approaches may have potential in the future to answer the unmet medical need. Furthermore, novel approaches are presented for potential eradication of latent HSV.

Keywords: HSV; antiviral therapies; clinical trials; drug development; herpes simplex virus; infections.

FIGURE 1

(A) Virion structure. The HSV virion consists of double‐stranded DNA encapsulated in a nucleocapsid. The nucleocapsid is surrounded by the inner and outer tegument. Surrounding the tegumented nucleocapsid is a lipid envelope with proteins. (B) HSV replication. Upon entry into the host cell, the tegument and nucleocapsid are released into the cytoplasm. The nucleocapsid releases the viral DNA into the host cell nucleus, where viral gene expression is initiated in a cascade‐like manner, enabling the viral DNA replication. New viral particles are then assembled and released from the host. (C) Mechanism of action of the current approved therapies.

FIGURE 2

Herpes simplex virus‐specific treatments in the clinical pipeline with known mechanisms of action.