For thousands of years herbs have been used as medicine by cultures all over the world. Today, a large variety of indigenous medicinal plants have been shown experimentally to possess promising anti-HIV activities. This has created optimism about the future of phyto-anti-HIV drugs development.
The Human Immunodeficiency Virus 1 (HIV-1), unknown a quarter of a century ago, is now the world’s leading cause of death among adults aged less than 60 years. And medicinal herbs have traditionally provided the pharmaceutical industry with some of its most important sources of ‘lead’ compounds in the search for new drugs and medicines.
At present, up to 40 to 50 per cent of modern drugs are derived from natural sources, using either the natural substance or a synthesised version, and are on sale at the pharmacies. Some 60 per cent of the 900 small-molecules (new chemical entities) introduced as drugs worldwide during 1981-2000 can be traced to, or were inspired by, natural product derivatives, 5 per cent of synthetic compounds with natural product-derived pharmacophores and 23 per cent mimics of natural products.
Over the last 30 years, a large number of plant species worldwide have been evaluated for their antiviral activities. These screens showed that some plants have a variety of chemical constituents — for instance, coumarins, flavonoids, tannins, alkaloids, lignans, terpenes, thiophenes, naphtha- and anthraquinones, polysaccharides, proteins and peptides, which have the ability to inhibit the replication cycle of various types of viruses. Some of these compounds belong to a wide range of different structural classes and may also be novel photochemicals.
Medicinal plant extracts could be therapeutically useful for several apparently unrelated syndromes by virtue of the synergistic effects of two or more components that complement each other in vivo and have restorative/activation functions. A chemically restorative activation function of anti-HIV-1 and anti-herpes simplex virus activity from pomegranate rind, Viburnum plicatum (leaves or flowers), Camellia sinensis (tea leaves) or acerpseudoplatanus (maple leaves) extracts was achieved in combination with ferrous sulphate.
When evaluating the antiviral activity of different chemical constituents extracted from medicinal plants, one must consider the effect of such variables as the extraction method, the parts of the plant used and the season of harvest.
The future
As far as virologists and a majority of the human population are concerned, HIV is among the world’s most urgent health challenges, one which we still have much to learn about. The consensus is that chemotherapy is a definite requirement.
Anti-retroviral drugs attack HIV in different ways and eventually some mutations to drug resistance will occur. Recently, researchers developed new types of drugs, such as the ones that block HIV from attaching to CD4 cells, and they are also trying to develop other types of drugs that will strengthen the body’s immune defence.
Since HIV is an RNA virus it is not subjected to the ‘proofreading’ that occurs during DNA transcription. In this regard, medicinal plant materials could play a role in a control strategy and in the past decade considerable attention has been paid to screening of various species of medicinal plant extracts for possible anti-HIV ‘inhibition replication’ of HIV-1.
It is well known that viral enzymes play a key role in triggering a disease. If viral enzymes could be neutralised, viral replication may not take place. The proteolytic processing of viral polyportein precursors by a viral proteinase is essential for maturation of the virus.
Therefore, designing specific inhibitors for HIV’s protease is an important objective. Many plants have been screened for their inhibitory activity on HIV viral replication. Nineteen Sudanese plant extracts were screened against HIV-1 protease (PR) using an HPLC assay method. Of the tested extracts, the methanol extracts of the desert plants Acacia nilotica (bark and pods), Euphorbia granulate (leaves), Maytenus senegalensis (stem-bark) and aqueous extracts of A. nilotica (pods) and M. senegalensis (stem-bark) showed considerable inhibitory effects against HIV-1.
Marked progress has been made recently concerning enzymatic activity of ‘ribosome-inactivating protein’ or RIPs. In an experiment trichobitacin, purified from the root tubers of Trichosanthes kirilowi, was found to greatly suppress syncytial cell formation induced by HIV-1 and to markedly reduce both expression of HIV-1 (p24) antigen (viral capsid protein) and the number of HIV antigen positive cells in acutely but not chronically HIV-1 infected culture.
Similar antiviral activities were also reported for a crude extract of a green algae, Caulerpa taxifolia, using the feline immunodeficiency virus (FIV) as a model for studying the HIV. The pokewood antiviral protein (PAP), a single-chain ribosome-inactivating protein (RIP) isolated from the spring leaves of Phytolacca americana, is another example of naturally occurring RNA-depurinating enzyme with broad-spectrum antiviral activity which is characterised by its ability to depurinate the sarcin ricin (S/R) loop of the large rRNA of prokaryotic and eukaryotic ribosome’s by cleaving supercoiled double-stranded DNA using the same active site that is required for depurination of rRNA.
Interest in PAP is growing due to its use as a potential anti-HIV-1 agent. More recently, 29kDa, 30kDa and 31kDa anti-HIV proteins were purified from the leaves of Phytolacca Americana, Momordica charantia and Gelonium multiflorum (anti-HIV-1 and HSV). These proteins are nontoxic to human sperm and female genital tract epithelial cells (even at a concentration of 2,000 times higher than its IC50 value against HIV-1) and possess clinical usefulness both as a non-spermicidal intravaginal microbicide and as a prophylactic antiviral agent that can inactivate infective viruses and virus-infected cells in human semen.
The promise of this natural product probably relates to a novel mechanism of interaction with reverse transcriptase (RT). It could conceivably play a role in combination therapy or even as a novel new anti-HIV phyto-chemo-type for drug development, in which inhibitors of HIV RT are important drugs for the treatment of Aids.
In this regard, water-soluble polar substances, aqueous extracts of aromatic herbs in Labiatae — such as Melissa officinalis, a family of Mentha x piperita ‘grapefruit mint’; Mentha x piperita var. crispa; Ocimum basilicum cv ‘cinnamon’; Perilla frutescens var. crispa f. viridis; Prunella vulgaris subsp. asiatica; and satureja montana — showed potent inhibitory effects against HIV-1 induced cytopathogenicity in MT-4 cells (with an ED of 16 microg/ml), inhibited giant cell formation in co-culture of Molt-4 cells with and without HIV-1 infection and possessed activity against HIV-1 RT.
Novel inhibitors of HIV-1 RT from the Malaysian rich rainforests Calophyllum spp, have been identified as inophyllum, calanolide A, and coumarins from Cal. inophyllum Cal. Lanigerum, Cal. teysmannii latex and Cal. cerasiferum vesque. A Japanese research group discovered Phyllanthus nituri’s HIV-1 RT inhibition properties with a simple water extract of the plant.
Research was carried out to isolate the active plant component, and in 1996 the Bristol-Myers Squibb Pharmaceutical Research Institute in the US isolated at least one of the constituents in the dried leaf of Phyllanthus niruri responsible for this activity — a novel compound which they named ‘niruriside’. Niruriside showed specific inhibitory activity against the binding of regulator of expression of the virion (REV) protein to REV-response element RNA with an IC50 value of 3.3 microM. However, niruriside did not protect CEM-SS cells from acute HIV infection at concentrations up to 260 microM using an XTT dye reduction assay.
Furthermore, the inhibition of the HIV-1 RT with modulatory role on immune cells was also reported for the Thai bitter gourd protein (MRK29) with molecular weight at 28.6 kD isolated from Momordica charantia ripe fruit and seed.
It should be noted that Iscador® Spezial (Weleda, AG Schwabisch Gmund Germany), an aqueous extract of Viscum album L (Loranthaceae) L. has been used for more than 80 years as an anti-cancer drug. Due to its immunomodulatory potential, it has also been applied in the treatment of HIV-positive and other people living with Aids in the form of the preparation Viscum album.
Conclusion
There are many plants and herb species that have the potential for novel anti-HIV activities and some novel anti-HIV compounds have already been isolated from medicinal plants, some compounds with viral protease inhibitor activity have been, or are currently undergoing various phases of clinical trial, and thus have the potential of becoming new anti-HIV pharmaceutical products. The promise of natural products probably relates to a novel anti-HIV-1 pure phyto-chemical as new drug leads or as starting material for semi-synthesis of modern drugs, in which inhibitors of HIV-1 RT are important drugs for the treatment of Aids.
Overall, current data and trends indicate that providing conventional anti-retroviral therapy to three million poor people by the end of 2005 is unlikely to fight off Aids effectively over the next three years. For this reason, increased efforts should be devoted to medicinal plants as sources of potent anti-HIV products.
The principal objective is to find safe and inexpensive herbaceutical anti-HIV drug which are as potent, or more so, than the present orthodox antiviral agents, expected to represent more promising candidates for people living with HIV or AIDS. The current candidate HIV vaccines that are also being considered for efficacy trials and are likely to act principally by reducing viral loads, hence reducing both transmission to sexual partners and progression to Aids.
As adolescents are bearing the brunt of the Aids epidemic in much of sub-Saharan Africa, we believe studies in this group are critical. It is argued that it is ethically justifiable to enroll adolescents in certain cases without seeking parental consent for adolescent participation in HIV research.
Dr Saeed is an HEC-designated national professor and Ms Hussain is a research scholar
