Prostratin's information

topic posted Mon, March 31, 2008 - 4:51 PM by  Unsubscribed

The University of California, Berkeley, has signed an agreement with the Samoan government to isolate from an indigenous tree the gene for a promising anti-AIDS drug and to share any royalties from sale of a gene-derived drug with the people of Samoa.

The agreement, announced today (Thursday, Sept. 30) in Apia, the capital of Samoa, supports Samoa's assertion of national sovereignty over the gene sequence of Prostratin, a drug extracted from the bark of the mamala tree (Homalanthus nutans). The drug currently is being studied by scientists around the world because of its potential to force the AIDS virus out of hibernation in the body's immune cells and into the line of fire of anti-AIDS drugs now in use.

"Prostratin is Samoa's gift to the world," explained Samoan Minister of Trade Joseph Keil. "We are pleased to accept the University of California as a full partner in the effort to isolate the Prostratin genes."

Despite Prostratin's promise as an anti-AIDS drug, its supply is limited by the fact that the drug has to be extracted from the bark and stemwood of the mamala tree. Researchers in the laboratory of Jay Keasling, UC Berkeley professor of chemical engineering, plan to clone the genes from the tree that naturally produce Prostratin and insert them into bacteria to make microbial factories for the drug. A similar technology is currently being explored to produce the anti-malarial drug artemisinin.

"A microbial source for Prostratin will ensure a plentiful, high-quality supply if it is approved as an anti-AIDS drug," said Keasling, who also is a faculty affiliate with the California Institute for Quantitative Biomedical Research (QB3) and head of the Synthetic Biology Department at Lawrence Berkeley National Laboratory. "We consider the actual gene sequences as part of Samoa's sovereignty, and every effort will be made to reflect this fact."

The agreement, signed by Prime Minister Tuila'epa Aiono Sailele Malielegaoi of Samoa and UC Berkeley's Vice Chancellor for Research Beth Burnside, gives Samoa and UC Berkeley equal shares in any commercial proceeds from the genes. Samoa's 50 percent share will be allocated to the government, to villages, and to the families of healers who first taught ethnobotanist Dr. Paul Alan Cox how to use the plant. The agreement also states that UC Berkeley and Samoa will negotiate the distribution of the drug in developing nations at a minimal profit if Keasling is successful.

"This may be the first time that indigenous people have extended their national sovereignty over a gene sequence" said Cox, director of the Institute for Ethnobotany at the National Tropical Botanical Garden in Hawaii. "It is appropriate, since the discovery of the anti-viral properties of Prostratin was based on traditional Samoan plant medicine."

The National Cancer Institute, which patented Prostratin's use as an anti-HIV drug, requires any commercial developer of Prostratin to first negotiate an equitable benefit-sharing agreement with Samoa.

"I think that UC Berkeley could set a precedent both for biodiversity conservation and genetic research by including indigenous peoples as full partners in royalties for new gene discoveries that result from their ancient medicines," Keasling said.

Keasling and a team of scientists led by Cox traveled to Samoa in early August to meet with leaders in three Samoan villages where the tree grows. They obtained the prior informed consent of the chief's council from each village to assist in the research in return for a share of the Prostratin gene proceeds. Dr. Gaugau Tavana, a Samoan educator from the National Tropical Botanical Garden, presented a Samoan-language PowerPoint presentation on genetic engineering in each village.

A previous royalty agreement on Prostratin was signed in 2001 by the Prime Minister of Samoa and the AIDS ReSearch Alliance, which is sponsoring clinical trials of Prostratin as an anti-AIDS therapy. That agreement would return 20 percent of any commercial profits arising from the plant-derived compound to the people of Samoa.

Keasling and his Samoan collaborators will freeze living cells from the mamala tree in liquid nitrogen so that extraction of the perishable RNA can be conducted in the laboratory. Then begins the process of tracking down the enzymes that actually build the molecule Prostratin.

Once Keasling has pinpointed the key enzymes and cloned their genes, he plans to insert the genes into a strain of E. coli bacteria that he has created to produce isoprenoid compounds like Prostratin. The product of more than 10 years of genetic engineering, the bacterial factories have already proven useful in producing precursors of the anti-malarial drug artemisinin, which he hopes to produce inexpensively for people in the developing world. The process also can be used to produce flavors and fragrances, many of which also are members of the class of chemical compounds called isoprenoids.
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  • Unsu...
    The story begins with Cox, who was once named a "Hero of Medicine" by Time magazine and is now the director of the Institute for Ethnobotany at the National Tropical Botanical Garden in Hawaii. Ethnobotanists study the ways in which indigenous cultures use plants for medicine. Which is why in 1987 Cox, then a researcher at Brigham Young University, was sitting in a thatched hut with an elderly Samoan woman named Epenesa Mauigoa. A tribal healer, she was describing for him the 121 herbal remedies she knew. Cox became particularly interested in remedy number 37. This called for boiling the bark from the mamala tree and giving the liquid to those suffering from what Samoans call fiva sama sama and we know as viral hepatitis.

    Samoan healer Ake Lilo prepares an antiviral extract from the bark of the mamala tree that he will used to treat hepatitis. The active ingredient, a chemical called prostratin, has also shown great potential for the treatment of AIDS.

    Drugs with potential antiviral properties are in high demand in the medical communities of developed nations, so Cox sent samples of remedy number 37 to the National Cancer Institute. In 1992, NCI researchers identified prostratin as the active ingredient in the mamala bark and found that it was indeed an effective treatment for hepatitis. However, they also found that it had powerful and unique therapeutic effects against AIDS: not only did prostratin prevent the AIDS-causing human immunodeficiency virus (HIV) from infecting human cells, it also forced dormant HIV virus particles out from hibernation within human immune cells, where they are protected from virus-killing medicines.

    Today's best anti-AIDS drugs can reduce a patient's HIV populations to safe levels, but as soon as the patient stops taking the drugs, dormant viruses emerge from their immune cell sanctuaries and quickly restore HIV populations to dangerous levels. Prostratin flushes out these "viral reservoirs" so that anti-AIDS drugs can eradicate the HIV population entirely. What's more, unlike other compounds from the same chemical family, which have been known to promote the growth of cancerous tumors, prostratin was shown to be a tumor suppressor.

    Preserving the mamala tree population in Samoa was a critical first step, but there is still a crucial need to be able to mass-produce prostratin in quantities far beyond what the bark and stemwood of the trees could supply. Enter Keasling and his synthetic biology research group, who have opened the door to adding new genes to E. coli bacteria by creating an E. coli strain with a new and specially designed metabolic pathway.

    Genetically engineered strains of Escherichia coli, the common bacterium, can be transformed into living factories that can cheaply synthesize and mass-produce disease-fighting drugs.

    Prostratin is a member of the huge isoprenoid family of chemical compounds, which are used in a wide variety of applications including as anti-cancer and anti-malarial drugs — plus as an assortment of flavor and fragrance additives. Genetic control mechanisms within the E. coli's natural metabolic pathway would interfere with the bacteria's ability to synthesize isoprenoid compounds, but Keasling and his colleagues get around this barrier by giving their E. coli strain a second metabolic pathway derived from yeast. This alternate pathway can be used to transform the E. coli into living factories designed to mass-produce a desired isoprenoid.

    Keasling and his research group first used their engineered strain of E. coli to produce a precursor to artemisinin, one of the most promising of all the antimalarial drugs. The success of this work led Keasling to Cox and his work with prostratin. Artemisinin and prostatin both belong to the terpene class of isoprenoids.

    "The basic superstructure of the bug we engineered to produce the antimalarial drug will work for producing prostratin," says Keasling. "Of course, we will need to add a few additional genes, but having the basic structure in place will save us both time and money."
    • Unsu...
      Two more plants of intrest for drug therapy.

      (Ancistrocladus korupensis)

      Tropical Rainforest Vine is HIV Positive

      Ancistrocladus meaning ‘hooked branch’ is a rare, slender, sinewy vine with ovate leaves and curly tendrils. The plant in question differs from other forms of Ancistrocladus, whose leaves curl slightly under at the base (‘revolute’), and has young leaves of a chimney-brick red colour with the undersides of the older leaves having an unusual yellowish tint. The plant grows in limited abundance in Korup National Park after which it is named and this ancient tropical rainforest lies along the sandy plains of Cameroon’s Atlantic coast.

      First gathered in March 1987 by Duncan W. Thomas, a researcher with the Missouri Botanical Garden, it wasn’t until the spring of 1991 that tests highlighted its action of inhibiting HIV from killing human cells. Thomas returned to the Cameroon in April 1991 and collected plentiful samples of leaves and bark. The alkaloid isolated, now known as michellamine B, was previously unknown (C46H48N2O8). Not only did it have a good ‘therapeutic index’ (that is, the amount needed to kill the virus was far less than that needed to kill the cell), but it also seemed to work against the other major strain of HIV called HIV-2, unusual for an aids drug. Importantly it also killed viral strains that resisted other new drugs.

      The compound is not dangerously toxic and dissolves in water, a property that makes it suitable as a medicine. Leaves of some samples, collected from the forest floor, have produced more than 2 to 3% dry weight of michellamine B and since the leaves are still potent after having fallen, there is no need to kill the plant to harvest the drug. Furthermore, the alkaloids do not degrade easily when the leaves are dried and stored.

      Many field studies are underway to ensure the availability of the plant since it does not grow abundantly in the wild and nurseries for transplanted seedlings have now been established in the
      in the Cameroon near Yaounde and near the Korup reserve. A point to note is that the plant was not used in local medicine and its discovery is owed to random screening. These facts underscore the need to preserve the biodiversity of tropical rainforests if simply only as a source of medicines for future diseases and viruses.


      (Calophyllum lanigerum)

      Mangosteen Relative As Potential Anti-AIDS Drug

      Calophyllum is a genus of the Guttiferae family and so a relative of the Malaysian local fruit tree that produces mangosteen. Calophyllum lanigerum is an unremarkable, medium sized tree that grows in the forests of Sarawak, Malaysia. Samples of it were collected in 1987 by a British botanist in association with the Arnold Arboretum of Harvard University and it was one of 800 plants sent back to NCI from S.E.Asia for testing during a period of about 5 years. Due to backlog, it was to be four years later before tests were finally completed and it was found to be effective against AIDs. Not only did it protect cells completely from HIV but also no resistant virus sprang to destroy the action, a common difficulty with plants that appear to produce results.

      Found growing near a river called Batang Kayan in South Sarawak, it was identified as Calophyllum lanigerum var. austrocoriaceum. The compound that NCI managed to isolate, they called Calanolide (later Calanolide-A). However, on eventually returning to the scene to rediscover the tree, they found only a tree stump. It had been logged. During this field trip, samples of another species of calophyllum, Calophyllum teysmannii var. inophylloide were collected for testing by the NCI. Analysis was to show it contained the almost identical compound Costatolide, later to be re-classified as Calanolide-B, which also killed the HIV virus but was not as powerful as the original. However, Calanolide can only be extracted in very low yields from the twigs and leaves of the tree, whereas Costatolide, is extracted from the latex. Since latex is tapped, the trees would be conserved and a continuous supply of the raw material easily available.

      By 1998, NCI was ready to advance to clinical tests and had requested a substantial amount of the latex. Trial planting of the two species has been initiated and in Sarawak, the joint venture company Sarawak MediChem Pharmaceuticals Inc has been set up to investigate, the primary clinical development of Calanolide for the treatment of HIV as well as the development of other drugs which display anti-viral properties.Cameroon near Yaounde and near the Korup reserve. A point to note is that the plant was not used in local medicine and its discovery is owed to random screening. These facts underscore the need to preserve the biodiversity of tropical rainforests if simply only as a source of medicines for future diseases and viruses.

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