In Western Australia, where it grows wild, people call the low,flowering shrub "smoke bush." At the National CancerInstitute's (NCI) Laboratory of Drug Discovery R&D, biochemicalpharmacologist Michael Boyd terms the plant's activecomponent, conocurvone, "a new lead compound with novelstructure and hopefully novel means of anti-HIV activity."
And at the National Institutes of Health's Office of TechnologyTransfer (OTT), licensing specialist Steven Ferguson ismanaging an offer of exclusive, royalty-bearing rights tocommercialize this exotic AIDS therapeutic.
Last week, OTT forwarded to the Federal Register a noticeinviting bids from companies interested in bringing to marketfuture conocurvone-based drugs protected by NIH's pendingpatent, "Antiviral Naphthoquinone Compounds, Compositionsand Uses."
In its July 28 issue, the Journal of the American ChemicalSociety broke the story of the promising natural product in apaper titled "Structure, Absolute Stereochemistry, andSynthesis of Conocurvone, a Potent, Novel, HIV-InhibitoryNaphthoquinone Trimer from a Conospermum (plant) species."
NCI's Boyd is the lead author of that article, which describesthe chemical synthesis and in vitro testing of the plant'sorganic extract.
Boyd started his drug-discovery laboratory five years ago inFrederick, Md., to screen natural products for anti-HIV andanti-cancer activity. The facility tests 400 samples a week forpossible anti-tumor effects, and 200 to 300 with apparent usein fighting AIDS. In the latter category was a bundle of driedstems, leaves and flowers collected in 1981 from the Gairdnermountains of Western Australia by U.S. Department ofAgriculture botanist Richard Spjut. At that time, his search wasfunded by the U.S. War on Cancer.
Today, Spjut identifies little-known plants at the USDA'sSystemic Botany and Mycology Laboratory in Beltsville, Md. Adecade ago he fixed on Western Australia as a high-potentialarea for finding medicinal plants.
"NCI surveys have shown that plants in drier, more aridenvironments have higher percentages of cytotoxicity or anti-tumor activity compared to those of rain forest regions," Spjuttold BioWorld.
The smoke bush was one of 758 botanical samples from 450different species that he dug up in the sand heath vegetationarea up-country from Perth between late August and the endof October 1981, and brought back to NCI.
"It's a very attractive plant," he recalled, "with a cluster ofwhite, cottony flowers on top of a long, bare stem. You can spotthem from 300 or 400 meters away, for which reason we coulddo an aerial reconnaissance. I estimate there are 50 million ofthe plants up there."
Nonetheless, the botanist emphasized, "botanically, it's still anunknown species."
"A serendipitous combination of events led to the shrub'srediscovery," Boyd told BioWorld. "Back when Spjut collectedhis samples, nobody even knew what AIDS was."
Put through the laboratory's basic, primary in vitro screen forHIV-inhibition and cell protection, conocurvone came up with a"quite impressive therapeutic index," Boyd said. Compared withthe "tens of thousands" of other candidate compounds his labhas identified and isolated over the past five years,"conocurvone is a very intriguing compound," he said.
"Any time we come up with something that appears to bereasonably potent and good in vitro at least, and doesn't appearto be acting by a mechanism we're already familiar with, Ithink it's a legitimately exciting lead," he said. But Boydcautions that "in in vivo studies, the toxicity profile might bequite different."
As the ACS journal reported, "Conocurvone completelyinhibited the killing of the human T-lymphoblastic target cellsby HIV-1 and essentially halted HIV-1 replication." So did thecompound's chemically synthesized analog. "We were able toeffect only a very small-scale synthesis of the compound," Boydsaid. "Whether or not we have the capacity to produce it (inquantity) is uncertain at the present time."
He and his group are now "vigorously" trying to elucidate thecompound's mechanism of action.
"The bioassay we use in initial stages of this discovery processconsist of the AIDS virus and suitable target cells that we caninfect with the virus," he explained. "These cells arereproducibly killed by the virus over a certain number of days.In essence, what we are looking for is the ability of the extract,or fraction or pure compound, to prevent HIV's killing effect.
"Once we isolate a pure compound, after that initial bioassayscreen, we take a more sophisticated and detailed look at itsanti-cytopathic activity and whether in fact the compound notonly prevents cell killing but also prevents viral replication," hesaid. "At that stage, we proceed with further detailed study toelucidate the mechanism of action and the effects of thecompound over a much broader range of viral strains andtarget cells."
What about biosynthesizing a genetically engineered version ofconocurvone? Boyd said no such work is under way in his lab,and "the expertise in that respect, particularly regarding the(smoke bush) source plant, likely resides more in WesternAustralia.
"We have an active scientific collaboration growing as wespeak," he continued, "with the Western AustralianConservation and Land Management scientists. Certainly theyhave tremendous botanical, economic and biological expertise.Excellent chemists as well as biologists engaged in work withconocurvone."
He noted that "news of this discovery is still very fresh," and atthis point the Australian scientists and ecologists are workingto determine the extent and sustainability of the natural plantsource. "If the conocurvone can be mass-produced whilepreserving and managing the plant appropriately," Boyddeclared, "that would be a big break in terms of immediateprospects for further preclinical drug research."
Welcoming the OTT licensing offer, Boyd expressed his personalopinion that "it would be of considerable value for acommercial partner to become involved, so we can see thepossibility of getting something other than U.S. taxpayers'salaries involved in the development of an exciting agentdiscovered in a federally funded program."
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.