Current lead natural products for the chemotherapy of human immunodeficiency virus (HIV) infection
Authors: Erik De Clercq
Journal: Medicinal Research Reviews (2000)

A large variety of natural products have been described as anti-HIV agents, and for a portion thereof the target of interaction has been identified. Cyanovirin-N, a 11-kDa protein from Cyanobacterium (blue-green alga) irreversibly inactivates HIV and also aborts cell-to-cell fusion and transmission of HIV, due to its high-affinity interaction with gp120. Various sulfated polysaccharides extracted from seaweeds (i.e., Nothogenia fastigiata, Aghardhiella tenera) inhibit the virus adsorption process. Ingenol derivatives may inhibit virus adsorption at least in part through down-regulation of CD4 molecules on the host cells. Inhibition of virus adsorption by flavanoids such as (−)epicatechin and its 3-O-gallate has been attributed to an irreversible interaction with gp120 (although these compounds are also known as reverse transcriptase inhibitors). For the triterpene glycyrrhizin (extracted from the licorice root Glycyrrhiza radix) the mode of anti-HIV action may at least in part be attributed to interference with virus-cell binding. The mannose-specific plant lectins from Galanthus, Hippeastrum, Narcissus, Epipac tis helleborine, and Listera ovata, and the N-acetylgl ucosamine-specific lectin from Urtica dioica would primarily be targeted at the virus-cell fusion process. Various other natural products seem to qualify as HIV-cell fusion inhibitors: the siamycins [siamycin I (BMY-29304), siamycin II (RP 71955, BMY 29303), and NP-06 (FR901724)] which are tricyclic 21-amino-acid peptides isolated from Streptomyces spp that differ from one another only at position 4 or 17 (valine or isoleucine in each case); the betulinic acid derivative RPR 103611, and the peptides tachyplesin and polyphemusin which are highly abundant in hemocyte debris of the horseshoe crabs Tachypleus tridentatus and Limulus polyphemus, i.e., the 18-amino-acid peptide T22 from which T134 has been derived. Both T22 and T134 have been shown to block T-tropic X4 HIV-1 strains through a specific antagonism with the HIV corecept or CXCR4. A number of natural products have been reported to interact with the reverse transcriptase, i.e., baicalin, avarol, avarone, psychotrine, phloroglucinol derivatives, and, in particular, calanolides (from the tropical rainforest tree, Calophyllum lanigerum) and inophyllums (from the Malaysian tree, Calophyllum inophyllum). The natural marine substance illimaquinone would be targeted at the RNase H function of the reverse transcriptase. Curcumin (diferuloylmethane, from turmeric, the roots/rhizomes of Curcuma spp), dicaffeoylquinic and dicaffeoylt artaric acids, L-chicoric acid, and a number of fungal metabolites (equisetin, phomasetin, oteromycin, and integric acid) have all been proposed as HIV-1 integrase inhibitors. Yet, we have recently shown that L-c hicoric acid owes its anti-HIV activity to a specific interaction with the viral envelope gp120 rather than integrase. A number of compounds would be able to inhibit HIV-1 gene expression at the transcription level: the flavonoid chrysin (through inhibition of casein kinase II, the antibacter ial peptides melittin (from bee venom) and cecropin, and EM2487, a novel substance produced by Streptomyces. α-Trichosanthin (from the root tubers of Trichosanthes kirilowii), MAP30 (from Momordi ca charantia), GAP31 (from Gelonium multiflorum), DAP30 and DAP32 (from Dianthus caryophyllus) would act as RIPs (ribosome-i nactivating proteins), suppressing the translation process. As glycosylation inhibitors, castanospermine and 1-deoxynojirimycin would interfere with the infectivity and secondary spread of HIV-1. And so would bellenamine [(R)-3,6-diamino-N-(aminomethyl)hexanamide] (from Streptomyces nashvillensis), albeit by an unknown mechanism. Hypericin and pseudohype ricin, two aromatic polycyclic diones from Hypericum triquetrifolium (St. Johnswort), could block HIV-1 infection through a variety of mechanisms (direct virucidal effect, inhibition of secondary virus spread, inhibition of virus budding, and inactivation of the preintegration complex). A number of miscellaneous compounds, including propolis, pokeweed antiviral protein, and michellamines inhibit HIV replication by mechanisms that still have to be resolved. Cyclosporins do so by preventing the interaction of cyclophil in A with the capsid gag proteins, thus blocking both a late event (assembly) and early event (nuclear localization of the preintegration complex) in the HIV replicative cycle. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 5, 323–349, 2000