Himalayan mountain natives call it the Heavenly Fruit Tree.
Botanists know the medicinal plant as Gelonium multiflorum, ofwhich the only non-Himalayan variety in the world grows on theseashores of Taiwan.
A company in Germany imports G. multiflorum seeds in quantityfrom India, as a brisk over-the-counter item, brewed as a panaceanbeverage, "to fight against certain tumors and viral infections _even the common cold."
So said pioneer molecular biologist Sylvia Lee-Huang, who added,"The Himalayan natives use it for everything." She told BioWorldToday, "In Taiwan during the long Japanese occupation, it was themost valuable tree they wanted to take back to Japan. However, itsmedicinal content is not as high as the Himalayan variety, which weuse in our work."
Lee-Huang, who teaches biochemistry at New York UniversitySchool of Medicine, heads a multicenter research effort, withHsiang-Fu Kung of the National Cancer Institute and Philip Huangof the National Institute of Child Health and Human Development.They have isolated salient peptides from G. multiflorum's seeds,cloned, mapped, synthesized and assayed the active molecule's gene,and crystallized its structure. Her hope is "to create shorter sequencesas mimetics for rationally designing a more efficient second-generation anti-viral and anti-tumor product."
Quadruple Anti-AIDS-Virus Punch
The group's paper in the Dec. 6 issue of Proceedings of the NationalAcademy of Sciences (PNAS) bears the self-explanatory title:Human immunodeficiency virus type 1 (HIV-1) inhibition, DNA-binding, RNA-binding, and ribosome inactivation activities in the N-terminal segments of the plant anti-HIV protein GAP31."
The 33-amino-acid protein, GAP31, (which stands for "geloniumanti-HIV protein of 31 kilodaltons") is "the shortest peptidenecessary and sufficient" to account for the synthesized compound'sfour putative antiviral activities: HIV-1 inhibition, DNA-binding,RNA-binding and ribosomal inactivation.
Chopping off inactive residues from this chain of amino acids, Lee-Huang said, identified a seven-moiety sequence responsible forDNA-binding, and a nine-unit length important to ribosomeinactivation. "Then, we further dissected this piece of oligopeptide tosee if we could distinguish between ribosomal and topologicalinactivation activity."
Lee-Huang is first inventor on U.S. patent number 5,317,009, issuedthis year under the title, "Anti-HIV proteins, GAP31, GAP30 andGAP32; DNA coding therefor, and therapeutic uses thereof."
Twisting DNA Helix Out Of Shape
"In the viral genome's topology," she explained, "its geometricstructure supercoiled DNA is the physiologically active form. Afterviral infection, it is integrated into the host genome for replication.Our compounds," Lee-Huang went on, "act specifically to relax thatsupercoiled DNA." This topological conversion, she emphasized, isirreversible.
"Lots of anti-tumor drugs," she pointed out, "also work in this way.They freeze the DNA into a certain topologically inactive form, thusinterfering with its further function." Moreover, "GAP31 works notonly for acute infections, but for already infected cells, and it alsoinhibits viral replication." While specifically effective against HIV-1-infected cells, PNAS reported, ". . . the peptides' inability toinhibit in vitro reverse-transcriptase activity implies that their anti-HIV action is different from that of 3' azido-3'-deoxythymidine(AZT) . . ."
"Another beauty of this GAP31," she observed, "is that, because ofits size, 31 kD, it cannot enter into normal, uninfected, healthy cells,which is why it has almost no detectable cytotoxicity in normalhuman cells, and none at all in experimental animals."
Still another plus is its apparent activity against viruses other thanHIV-1, as suggested by preliminary in vitro effects againstcytomegalovirus and hepatitis B.
With the full sequences of GAP31 responsible for DNA and RNAbinding in hand, Lee-Huang said, "We would like next to put thosepeptides into a clinical situation. My laboratory does basic research,so for that we need additional resources, and that's a long way off."
While pursuing further elucidation of the molecules' mechanisms,looking toward a second-generation drug, she said, "in the meantime,we have enough of the parent compound to do animal studies andclinical trials."
In addition, results obtained in Lee-Huang's laboratory, since shesubmitted her paper to the current PNAS last summer, document [inthe just-issued International Journal of Oncology, Vol. 5, pp. 1171-1176] GAP31's anti-cancer activity, as tested with the National Cancer Institute's tumor-screening program on a panel of breast, prostate, lung, liver andbrain malignancies. Supporting this bonus anti-cancer activity, shenotes that "A lot of tumor cells are virally transformed cells." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.