Journal of Applied Microbiology 2003, 95, 412–427 doi:10.1046/j.1365-2672.2003.02026.x A REVIEW Novel antiviral agents: a medicinal plant perspective S.A.A. Jassim and M.A. Naji Department of Microbiology, Zayed Complex for Herbal Research and Traditional Medicine, General Authority for Health Services of Emirate of Abu Dhabi, Abu Dhabi, UAE 2002/97: received 4 March 2002, revised 4 April 2003 and accepted 16 April 2003 1. Summary, 412 6. Phyto-therapy and clinical trial, 419 2. Introduction, 412 7. The effect of synergetic combination of medicinal plants 2.1 Viral infection control, 413 in the potency of antiviral activity against selected 2.2 Overview of medicinal plants worldwide, 413 viruses, 421 3. Antiviral activity of herbal medicine against selected 8. Aspects of synergetic combination of medicinal plants viruses, 413 with orthodox drugs for alleviating viral infection, 421 4. Marine herbs and antiviral activities, 414 9. Future prospects, 422 5. The common classes of antiviral compounds present in 10. Conclusion, 423 medicinal plants, 414 11. References, 423 capable of acting therapeutically in various viral infections 1. SUMMARY has raised optimism about the future of phyto-antiviral Several hundred plant and herb species that have potential agents. As this review illustrates, there are innumerable as novel antiviral agents have been studied, with surpris- potentially useful medicinal plants and herbs waiting to be ingly little overlap. A wide variety of active phytochem- evaluated and exploited for therapeutic applications against icals, including the flavonoids, terpenoids, lignans, genetically and functionally diverse viruses families such as sulphides, polyphenolics, coumarins, saponins, furyl com- Retroviridae, Hepadnaviridae and Herpesviridae. pounds, alkaloids, polyines, thiophenes, proteins and peptides have been identified. Some volatile essential oils 2. INTRODUCTION of commonly used culinary herbs, spices and herbal teas have also exhibited a high level of antiviral activity. Viruses are obligate intracellular parasites, which contain However, given the few classes of compounds investigated, little more than bundles of gene strands of either RNA or most of the pharmacopoeia of compounds in medicinal DNA, and may be surrounded by a lipid-containing envelope plants with antiviral activity is still not known. Several of (Wagner and Hewlett 1999). Yet viruses are far from simple. these phytochemicals have complementary and overlapping Unlike bacterial cells, which are free-living entities, viruses mechanisms of action, including antiviral effects by either utilize the host cell environment to propagate new viruses. inhibiting the formation of viral DNA or RNA or They use the reproductive machinery of cells they invade inhibiting the activity of viral reproduction. Assay meth- causing ailments as benign as a common wart, as irritating as ods to determine antiviral activity include multiple-arm a cold, or as deadly as what is known as the bloody African trials, randomized crossover studies, and more compro- fever. The viruses that cause Lassa fever and Ebola fever and mised designs such as nonrandomized crossovers and pre- the retrovirus that causes acquired immunodeficiency syn- and post-treatment analyses. Methods are needed to link drome (AIDS) are examples that researchers call hot agents – antiviral efficacy/potency- and laboratory-based research. viruses that spread easily, kill sometimes swiftly, and for Nevertheless, the relative success achieved recently using which there is no cure or vaccine (Peter 1994). medicinal plant/herb extracts of various species that are Viruses have numerous invasion strategies. Each strain of virus has its own unique configuration of surface molecules (Wagner and Hewlett 1999). These surface molecules work Correspondence to: Sabah A.A. Jassim, Head of Microbiology Department, Zayed Complex for Herbal Research and Traditional Medicine, PO Box 29300, Abu Dhabi, like keys in a lock, enabling viruses to enter into hosts by United Arab Emirates (e-mail: [email protected]). precisely fitting the molecules on their surfaces to those on ª 2003 The Society for Applied Microbiology NOVEL ANTIVIRAL AGENTS 413 the membranes of target cells. The success of viruses in Virtually all cultures around the globe have relied evolution has been assured by four general attributes: historically, and continue to rely on medicinal plants for genetic variation, variety in means of transmission, efficient primary health care. There is currently a worldwide upsurge replication within host cells, and the ability to persist in the in the use of herbal preparations and the active ingredients host (Wagner and Hewlett 1999). As a consequence viruses isolated from medicinal plants in health care. Natural have adapted to all forms of life and have occupied products from plants traditionally have provided the phar- numerous Ôecological nichesÕ resulting in widespread dis- maceutical industry with one of its most important sources eases in humans, livestock and plants. of ÔleadÕ compounds and up to 40% of modern drugs are derived from natural sources, using either the natural substance or a synthesized version. 2.1 Viral infection control Control of viral infections, like any other kind of infection 3. ANTIVIRAL ACTIVITY OF HERBAL control, can be affected either as a prophylactic (protective) MEDICINE AGAINST SELECTED VIRUSES measure or therapeutically, in order to control and alleviate a viral infection, which has already been established in the Many traditional medicinal plants have been reported to have host. Unlike bacterial, fungal and parasitic infections, viruses strong antiviral activity and some of them have already been are not autonomous organisms and therefore, require living used to treat animals and people who suffer from viral cells in which to replicate. Consequently, most of the steps in infection (Hudson 1990; Venkateswaran et al. 1987; Thyag- their replication involve normal cellular metabolic pathways, arajan et al. 1988, 1990). Research interests for antiviral agent and this makes it difficult to design a treatment to attack the development was started after the Second World War in virion directly, or its replication, without accompanying Europe and in 1952 the Boots drug company at Nottingham, adverse effects on the infected cells (Wagner and Hewlett England, examined the action of 288 plants against influenza 1999). Fortunately, we now know that many viruses have A virus in embryonated eggs. They found that 12 of them unique features in their structure or in their replication suppressed virus amplification (Chantrill et al. 1952). During cycles, and these constitute potential targets. In fact, the last 25 years, there have been numerous broad-based successful antiviral chemotherapy has been achieved against screening programmes initiated in different parts of the the herpes virus with the development of acycloguanosine, globe to evaluate the antiviral activity of medicinal plants for sold as ÔacyclovirÕ, because it interferes with certain key viral in vitro and in vivo assays. Canadian researchers in the 1970s enzymes that have distinctive affinities for different nucleo- reported antiviral activities against herpes simplex virus tide analogues (Wagner and Hewlett 1999). Viral enzymes (HSV), poliovirus type 1, coxsackievirus B5 and echovirus 7 play a key role in triggering disease. If viral enzymes could be from grape, apple, strawberry and other fruit juices (Kono- neutralized, viral replication would not take place. The walchuk and Speirs 1976a,b, 1978a,b). proteolytic processing of viral polyprotein precursors by a One hundred British Columbian medicinal plants were viral proteinase is essential for maturation of the virus. screened for antiviral activity against seven viruses Designing specific inhibitors for each of viral protease is thus (McCutcheon et al. 1995). Twelve extracts were found to a desirable objective. have antiviral activity at the concentrations tested. The extracts of Rosa nutkana and Amelanchier alnifolia were very active against an enteric corona virus. A root extract of 2.2 Overview of medicinal plants worldwide Potentilla arguta and a branch tip extract of Sambucus There is currently a large and ever-expanding global racemosa completely inhibited respiratory syncytial virus population base that prefers the use of natural products (RSV). An extract of Ipomopsis aggregata demonstrated good in treating and preventing medical problems. This has activity against parainfluenza virus type 3. A Lomatium influenced many pharmaceutical companies to produce new dissectum root extract completely inhibited the cytopathic antimicrobial formulations extracted from plants or herbs. effects of rotavirus. In addition to these, extracts prepared At present, plant and herb resources are unlimited, as far from Cardamine angulata, Conocephalum conicum, Lysichiton as the search for useful phyto-chemicals is concerned; but americanum, Polypodium glycyrrhiza and Verbascum thapsus these resources are dwindling fast, due to the onward march exhibited antiviral activity against herpes virus type 1. of civilization. We have barely scraped the surface in our The extracts of 40 different plant species have been used efforts to exploit the plant world for antimicrobials (namely, in traditional medicine and were investigated for antiviral antiviral, antibacterial and antifungal compounds). Although activity against a DNA virus, human cytomegalovirus a significant number of studies have used known purified