Over the centuries herbal medicinal products formed the basis of medicaments in Africa, China, India and in many other civilisations. Traditional healers have long used herbal products to prevent or to cure infectious conditions but scientific interest in natural antivirals is more recent, spurred on by the rapid spread of emerging and re-emerging infectious diseases. Additionally the rapid rate of species extinction leads to irretrievable loss of structurally diverse and potentially useful phytochemicals, compounds which are often species/strain-specific with diverse structures and bioactivities, synthesised mainly for defence against predators.
The herpes virus
The herpes virus belongs to Herpesviridae, a family of DNA viruses that cause diseases in humans and animals. There are eight distinct viruses in this family, known to cause disease in humans. Viruses of the herpes group are morphologically indistinguishable, share many common features of intracellular development, but differ widely in biological properties. All human herpes viruses (HHV) contain a large double-stranded, linear DNA with 100-200 genes encased within an icosahedral protein capsid wrapped in a lipid bilayer envelope, called a virion. Following the binding of viral envelope glycoproteins to host cell-membrane receptors, the virion is internalised and dismantled, allowing viral DNA to migrate to the host cell nucleus, where viral DNA replication and transcription occurs.
One replication cycle of herpes virus depends upon a number of steps:
• virion entry
• expression of immediate-early (a) genes such as those for infected cell proteins (ICP) 0 and 4
• early (β1, β2) genes including DNA polymerase and thymidine kinase
• late genes (γ1, γ2) containing glycoprotein B (gB), C (gC) and ICP5
• unpaired DNA replication.
During symptomatic infection, infected cells transcribe lytic viral genes, but sometimes a small number of latency associated transcript (LAT) genes accumulate, which help the virus to persist in the host cell indefinitely. The primary infection is a self-limited period of illness, but long-term latency is symptom-free. Following reactivation, transcription of viral genes switches from LAT to multiple lytic genes that lead to enhanced replication and virion production.
Herpes viruses cause localised skin infections of the mucosal epithelia of the oral cavity, pharynx, oesophagus and the eye, or genitals, depending upon the type involved. Moreover, the herpes viruses establish latent infections that can be periodically reactivated, and sometimes produce serious infections of the CNS, such as acute encephalitis and meningitis, and can be fatal in immune-deficient patients. The immediate-early genes of herpes simplex virus (HSV) can also activate the genes of HIV, varicella-zoster virus or human papillomavirus type 18, causing a significant risk factor for transmission of HIV/AIDS. The herpes virus can also lead to scarification, a major cause of blindness in developing nations.
HSV-2 is also known as an oncogenic virus as it can convert infected cells into tumour cells (Habif, 2004). The search for selective antiherpes virus agents is an urgent need as the problems such as viral resistance, conflicting efficacy in recurrent infection and immunocompromised patients with available antiherpes drugs remain unresolved. Moreover, herpes viruses (HSV-1 and HSV-2) spread silently (asymptomatic), cause opportunistic infections in immunocompromised patients, and develop resistance to acyclovir.
Control of herpes virus infection
The herpes virus causes a lifelong infection with high morbidity, and is underdiagnosed because of its mild and asymptomatic nature. herpes simplex virus alone affects more than one third of the world’s population and is responsible for a wide array of human disease. Before the 1970s, when acyclovir was introduced as an antiviral drug, cutaneous herpes simplex virus infection was managed with drying agents and other local care. Newer antiviral drugs such as famciclovir and valacyclovir with once-daily dosage benefits have emerged during the past several years but are more expensive. Although no cure is available to date, the nucleoside analogue acyclovir is widely used, as it is selectively phosphorylated by thymidine kinase enzyme in infected cells. However, acyclovir-resistant herpes virus has been isolated in immunocompromised patients and is not suitable in neonatal infections. Therefore, new antiherpes virus agents are highly desirable.
The development of antiherpetic agents from herbal sources is less explored probably because there are very few specific viral targets for small natural molecules. However, studies have shown that a variety of compounds inhibit the replication of herpes viruses, e.g. phloroglucinol, anthraquinones, polysaccharides, triterpenes and saponins and polyphenols. A topical preparation from Glycyrrbiza glabra (liquorice root) containing triterpene glycyrrhetinic acid (Glycyrrhizin) used for the prevention and treatment of herpes outbreaks was found to inhibit acyclovir-resistant HSV-1, by induction of CD4 + T cells.
Oryzacystatin from rice plant (Oryzae sativa) showed in-vitro and in-vivo anti-HSV-1 activity by inhibiting proteinase enzyme of herpes viruses. When 19 plant-derived compounds were tested by plaque reduction assay against HSV-2, it was found that eugenol, cineole, curcumin and carrageenan lambda type IV (ED50 = 7.0 mg/mL), provided significant protection (P<0.05) in intra-vaginal HSV-2-mice infected and guinea pigs. All these findings indicated that the herbal products are still potential sources for new antiherpetic agents. Owing to their amazing structural diversity and broad range of bioactivities, herbal medicinal products can be explored as a source of complementary antiherpetic agents, as many of them inhibit several steps of replication cycle and certain cellular factors of herpes viruses.