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Can Ethnophamacology Contribute to Antiviral Drugs

Can Ethnophamacology Contribute to Antiviral Drugs

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Journal of Ethnapharmacofogy, 32 (1991) 141-153
Elsevier Scientific Publishers Ireland Ltd.141
Can eth~opha~acology contribute toantiviral drugs?the development of
Arnold J. Vlietinck and Dirk A. Vanden Berghe
Faculty of Medicine, University
(UIA), B-2610 Antwerp (Belgium)
In recent years, many compounds having potent antiviral activity in cell cultures and in experimental animals have been detected,but only a few have been approved by Western health authorities for clinical use. Nevertheless, some of these compounds are currentlyundergoing either preclinicat or clinical evaluation, and perspectives for finding new interesting antiviral drugs are promising. Amongthese antiviral substances are several natural compounds isolated from plants used in traditional medicine including polysaccharides,Bavonoids, terpenes, alkaloids, phenolics and amino acids. Some of these plant compounds exhibit a unique antiviral mechanism ofaction and are good candidates for further clinical research. What follows is a brief summary of the selection methods of plants forantiviral screening and in vitro and in vivo assays, which are currently used for detecting this activity in plant extracts. The importanceof the plant kingdom as a source of new antiviral substances will be illustrated by presenting a survey on plant-derived antirhinovirusand anti-HIV agents.
The identification of a retrovirus, human im-munode~cien~y virus (HIV) as the causative agentof AIDS (acquired immunedeficiency syndrome),the steadily increasing incidence of various viralinfections caused by viruses such as herpes simplexvirus (HSV),varicella-zoster virus (VZV),cytomegalovirus (CMV) and Epstein-Barr virus(EBV), in immunode~cient patients, the increasingevidence for the pathogenic role of a number ofviruses viz. human papilloma virus (HPV) in thepathogenesis of primary hepatocellular carcinomaand the socioeconomic impact of virus infectionsof the respiratory tract (influenza, adeno, coronaand rhinoviruses) and gastrointestinal tract(rotaviruses) have all been important factors inboosting the search for new antiviral agents andnew modalities of antiviral chemotherapy.Although many compounds having potent an-tiviral activity in cell cultures and in experimental
Presented at the First International Congress on Ethnophar-macology, Strasbourg, 5-9 June, 1990.
Correspondence to:
Arnold J. Vlietinck, Faculty of Medicine,University of Antwerp (UIA), B-2610 Antwerp, Belgium.
animals have been detected, at present, only sevensynthetic compounds and alpha interferon havebeen approved by the FDA for therapy of viral in-fections in humans. Four of these compounds arefor the therapy of infections caused by members ofthe herpes family including 5-iodo-2 ‘deoxyuridine(idoxuridine), 5-trifluoromethyl-2’-deoxyuridine(trifluridine), 9-fi-D-arabinofuranosyladenine (vid-arabine) and 9-(2-hydroxyethoxymethyl)guanine(acyclovir).A fifth compound, I-aminoadamantane (aman-tadine), is approved for the therapy and pro-phylaxis of respiratory infections caused by the in-fluenza virus A. A sixth antiviral agent,l-~-~r~bofuranosyl-l,2,4-triazole-3-carboxamide(ribavirin) is approved for therapy of severe respi-ratory infections in children caused by the respira-tory syncytial virus. The seventh antiviral agent,3 ‘-azido-3 ‘-deoxythymidine (zidovudine, AZT),has been approved for therapy of AIDS. Alpha in-terferon has been approved for treatment ofgenital warts caused by papilloma virus and for thetherapy of hairy cell leukemia and Kaposi sarcoma(Prusoff et al., 1989). The chemical structures ofthe FDA-approved drugs are given in Fig. 1.
0378-8741~03.50 0 1991 Elsevier Scientific Publishers Ireland Ltd.Published and Printed in Ireland
‘a‘ -CHsOH
Fig. 1. Chemical structures of antiviral drugs approved by the FDA for use in humans. I, Amantadine; 2. idoxuridine; 3, trifluridine;4, acyclovir; 5, vidarabine; 6, ribavirin; 7, zidovudine (AZT).
None of these drugs, however, is without tox-icities and hence there is a strong need not only toimprove the actual antiviral armamentarium, butalso to find an effective therapy of viral infectionsfor which at present no clinically useful drugs orvaccines are available.There is also a need for finding new substanceswith extracellular virucidal activity, since many ofthe existing antiseptics and disinfectants fail to killall pathogenic viruses after a 5-min exposure timeat room temperature (Springthorpe et al., 1986;Vanden Berghe et al., unpublished results). Suchcompounds could be very useful to diminish thetransfer of viable viruses from infected individualsto uninfected ones, to objects or to the air ofenclosed spaces.Therefore, all possible approaches towards thedevelopment of new antiviral and virucidal drugsshould be pursued. Besides the rational approach,which in its ultimate form requires a sophisticatedknowledge of both the target structure, e.g. the ac-tive site of an enzyme, a receptor, a macromoleculesuch as DNA, RNA or a regulatory protein andthe compound to interact with it, the emperical ap-proach still remains valuable (Prusoff et al., 1986;De Clercq, 1988; Montgomery, 1989). Systematicscreening of pure substances or extracts of variousorigins has resulted in the discovery of many activeleads. These substances can be improved byrepeated structure modification in the hope thatthe change being made will result in increasedpotency,selectivity,duration of action,
bioavailabiiity and reduced toxicity. By combiningstructure-activity relationships with computer-graphic model building, the sere~ndity approachcan even become a rational serependity approach(Prusoff et al., 1989).There are many sources of materials for an-tiviral testing, including pure synthetic and naturalsubstances of known structure and naturally oc-curring mixtures of the plant, animal and marineworld.The purpose of this communication is to discussand review the current activities in the area of me-dicinal plants and plant-derived products relatedto in vitro and in vivo preclinical evaluation forantiviral and virucidal activities.
Selection of plants for antiviral screening
Four basic methods are available for selectingplants for a screening programme to seek antiviralleads including: (1) random collection of plantsfollowed by mass screening; (2) selection based onethnomedical uses; (3) follow-up of existingliterature leads; and (4) chemotaxonomic ap-proaches (Suffness and Douros, 1979). The sameadvantages and disadvantages of the various ap-proaches to the selection of plants for screening todiscover anticancer activity can be associated withapproaches to discover antiviral activity in plants(WHO Report, 1989). All factors considered, ap-proaches (2) and (3) would seem to be the mostcost-effective for finding plants with antiviral pro-perties,Comparison of the different approaches showedthe selection method based on folklore to give afive-times higher percentage (about 25%) of activeleads, although, in some cases, the same activecompounds were isolated from botanically non-related active plants. On the other hand, thescreening of extracts from random collected plantsafforded more novel substances with antiviral pro-perties (Vanden Berghe et al., 1978; Ieven et al.,1982; Van Hoof et al., 1989). Since the screeningcapacity of our research group is rather limited, weprefer a selection of plants based on a combinedanalysis of ethnomedi~al, phytochemical, tax-onomical and toxicological data (Vanden Bergheet al., 1986).
Selection of in vitro antiviral tests for the screeningof plant extracts and natural products
As the methodology used in the determinationof the antiviral activity as well as the interpretationof the results have been virtually specific to eachlaboratory and are consequently not comparableto one another, simple procedures and guidelinesfor evaluating antiviral and/or virucidal activitiesof single componnds are urgently needed. This iseven more true for the antiviral testing of crude ex-tracts, containing a complicated mixture of dif-ferent compounds present in several proportions.Various cell culture-based assays are currentlyavailable and can be succesfully applied for the an-tiviral (A) or virucidal (V) determination of singlesubstances (S) or mixtures of compounds e.g. plantextracts (M). Antiviral agents interfere with one ormore dynamic processes during virus biosynthesisand are consequently candidates as clinicallyuseful antiviral drugs, whereas virucidal sub-stances inactivate virus infectivity extracellularlyand are rather candidates as antiseptics, exhibitinga broad spectrum of germicidal activities.Cost, simplicity, accuracy and reproductibilityare the key factors which should determine theselection of the assay system, but also selectivity,sociality and sensitivity should be taken into ac-count, especially for the testing of extracts. Werefer to the appropriate literature for an extensivereview of all factors influencing the design of an-tiviral chemotherapy experiments (Hermann, Jr.,1961; Kaufmann, 1965; Sidwell, 1986; VandenBerghe et al., 1986).The methods commonly used for evaluation ofin vitro antiviral activities are based on the dif-ferent abilities of viruses to replicate in culturedcells. Some viruses can cause cytopathic effects(CPE) or form plaques. Others are capable of pro-ducing specialized functions or cell transforma-tion. Virus replications in cell cultures may also bemonitored by the detection of viral products, i.e.viral DNA, RNA or polypeptides. Thus, the an-tiviral test selected may be based on inhibition ofCPE, reduction or inhibition of plaque formationand reducing virus yield or other viral functions(Hu and Hsiung, 1989; Vanden Berghe andVlietinck, 1991).

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