Anti-HIV drug from rainforest almost lost before its discovery
Rhett A. Butler, mongabay.com
September 13, 2005
Rainforest plants have long been recognized for their potential to provide healing compounds. Indigenous peoples of the rainforest have used medicinal plants for treating a wide variety of health conditions while western pharmacologists have derived a number of drugs from such plants.
Calanolide A is derived from Calophyllum lanigerum var austrocoriaceum, an exceedingly rare member of the Guttiferae or mangosteen family. Samples of Calophyllum lanigerum var austrocoriaceum were first collected in 1987 on an National Cancer Institute (NCI)-sponsored expedition in Sarawak, Malaysia on the island of Borneo. Once scientists determined that Calophyllum lanigerum var austrocoriaceum showed activity against HIV, researchers returned to the original kerangas forest near Lundu (Sarawak, Malaysia) to gather more plant matter for isolating the active compound. The tree was gone -- likely felled by locals for fuelwood or building material. The disappearance of the tree lead to mad search by botanists for further specimen. Good news finally came from the Singapore Botanic Garden which had several plants collected by the British over 100 years earlier. Sarawak banned the felling and export of Calophyllum shortly thereafter.
HIV has a life span that can be as short as about 1.5 days from assembly by an infected, effectively hijacked cell through infection of another cell back to assembly by the newly infected cell. HIV lacks proofreading enzymes to correct errors made when it converts its RNA into DNA via reverse transcription. Since the life time of HIV is short and the DNA copies are wildly diverse due to a high error rate HIV mutates very rapidly. Most of the mutations either are inferior to the parent virus (often lacking the ability to reproduce at all) or convey no advantage, but some of them are superior to their parent and can enable HIV to slip past defenses such as the human immune system and antiretroviral drugs. The best defense against resistance is to suppress HIV as much as possible because the more active copies there are, the more chance that a superior one will be made. This is natural selection in action.
Combinations of antiretrovirals work by increasing the number of obstacles HIV has to mutate around and by reducing the chances of a superior mutation by keeping the number of offspring low. If a mutation arises that conveys resistance to one of the drugs being taken, the other drugs will help suppress reproduction of that mutation. With rare exceptions, no individual antiretroviral drug has been demonstrated to suppress an HIV infection for long; these agents must be taken in combinations in order to have a lasting effect. As a result the standard of care is to use combinations of antiretroviral drugs.
Combinations of antiretrovirals are subject to positive and negative synergies. This limits the total number of combinations that are available to use. For example, taking ddI and AZT together does less than taking either one separately since they inhibit each other.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are a class of anti-HIV drugs that prevent healthy T-cells in the body from becoming infected with HIV. Approved NNRTIs include Viramune® (nevirapine) from Boehringer Ingelheim, Sustiva® (efavirenz) from Bristol-Myers Squibb, and Rescriptor® (delavirdine) from Pfizer. Most NNRTIs dramatically reduce viral load soon after the first dose is taken, but Calanolide A, for reasons that are not yet known, seems to have a delayed effect.
Due to the low prevalence of Calanolide A in Calophyllum lanigerum var austrocoriaceum (only 0.05% can be extracted from the twigs and leaves) Sarawak MediChem Pharmaceuticals, has developed and patented a process for the total synthesis of (+)-Calanolide A. Calanolide A is currently in clinical trials but is not yet approved by the FDA for use outside of clinical trials..
A related species, Calophyllum teysmannii var. inophylloide, produces a compound (Costatolide) that also exhibits activity against HIV. Costatolide, now known as (-)-Calanolide B, is present in the latex so that tree need not be felled in order to collect the compound. Calanolide B is in preclinical testing with the National Cancer Institute.