Once an AIDS virus binds to its target cell, there's no stopping it _yet. The HIV's next invasive move is to merge its viral envelope withthe human cell's membrane, as a prelude to penetration and infection.Help is on the way. The scaly bark of a common street tree in Francemakes a compound that can block the fusion of virus to cell, at least invitro. The secondary metabolite this European plane tree (Platanus)synthesizes is a triterpene _ a hydrocarbon with 30 carbon atoms.(One triterpene known to medical science is squalene, an intermediatein cholesterol synthesis.)Almost serendipitously, scientists at the French chemical andpharmaceutical giant, Rhone-Poulenc Rorer (R-PR), discovered thatbetulinic acid from the bark of that tree can foil the fusion step in theAIDS virus's assault on its target cell.The title of their report in yesterday's Proceedings of the NationalAcademy of Sciences (PNAS) says as much: "Triterpene derivativesthat block entry of human immunodeficiency virus type 1 into cells."Its principal author, Jean-Franois Mayaux, heads the HIV program atR-PR's research center in Vitry, France."In the course of our regular screening of natural products for usefulcompounds," Mayaux told BioWorld in a telephone interview, "weidentified one of these compounds. It initially had only a small activityagainst HIV."But as the PNAS paper recalled, "We unexpectedly detected aderivative bearing an 11-aminoundecanoic lateral chain, which . . . wasat least 10-fold more potent against HIV-1 in cellular infection assaysthan the original compounds."He and his associates chemically optimized this fusion-foiling effect byadding a fatty-acid side-chain to the original betulinic acid, and havesince produced and tested several hundred derivatives. They surmisethat "the target for these compounds is contained within, or interactswith, the HIV-1 envelope gp120/gp41 glycoproteins."Seeking those most suitable for pharmaceutical development,"Mayaux said, "we have studied and compared the potency and oralbioavailability of these derivatives, and their activity not only onlaboratory strains of HIV, but also in primary [real-life] isolatesreplicating in human peripheral blood mononuclear cells."Their derivatives also block fusion between HIV-1-infected cells andthose not yet affected. This suggests that the compounds can act toprevent the virus from spreading in vivo. On the other hand, thederivatives appear to be specific to HIV-1 strains, with no effect onHIV-2.Mayaux acquired his experimental viral strains from the world'spreeminent AIDS researchers: Luc Montagnier of the Pasteur Institute,Robert Gallo at the U.S. National Cancer Institute, and Britain'sMedical Research Council.Until now, only certain monoclonal antibodies and peptides are knownto prevent viral envelopes from fusing with target cell membranes.These, Mayaux said, are entirely unsuited to therapeutic use.Peptides, he explains, are "intrinsically very unstable in vivo, are notorally bioavailable, and cannot be administered by any procedure."Also, peptidic compounds are not immunologically neutral, so couldnot in any event be given to a patient for long periods of time, "asunfortunately might be the case for AIDS."Antibodies are impractical for other reasons as well as immunological,Mayaux added, such as expense of large-scale manufacture."So the whole issue for us," he concluded, "is to select the most potent,bioavailable, easily synthesized non-peptidic derivative." He added,"We think we will be in a position in the very next few weeks to selectone of these compounds for further preclinical development."

-- David N. Leff Science Editor

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