Calanolide A is an experimental non-nucleoside reverse transcriptase inhibitor. This compound was extracted from the Calophyllum lanigerum, of variety austrocoriaceum, trees in Lundu, Malaysian state of Sarawak in 1992 by United States National Cancer Institute. Due to rarity of the raw materials and low yield of the active ingredient, total synthesis of the compound was devised in 1996. For the same reason, its sister compound -Calanolide B have been tauted as replacement. As a result of the discovery of Calanolide A, Sarawak Medichem pharmaceuticals company was established as a joint venture between US-based MediChem Research Inc and Sarawak state government. In 2006, Craun Research, a company established by Sarawak government, acquired Sarawak MediChem. In 2016, Craun Research announced the completion of Phase I clinical trials for Calanolide A.
History
In December 1986, Arnold Arboretum of the Harvard University in Massachusetts, requested permission from Sarawak state government to collaborate with Sarawak forest department to collect plants from Sarawak for phytochemical analysis. Permission was granted in May 1987. The plants collection project was part of the many expeditions launched by United States National Cancer Institute, to find new natural substances to treat cancer and AIDS infection. In September 1987, a botanist named John Burley went on a mission to collect plant samples from a swamp forest at Lundu, Sarawak, Malaysia. He and his team routinely collected a kilogram of fruits, leaves, and twigs from each type of plant they encountered. Part of the samples were sent to NCI for analysis and the other part was sent to Harvard University Herbaria for safekeeping for future research. A sample which was labelled "Burley-and-Lee-351" although showing no effect when tested against cancer cells in cultures, was able to stop viral replication when tested against HIV-1 virus. The sample was later determined to have come from a tree identified as Calophyllum lanigerum of variety austrocoriaceum. Sarawak Forest Department was informed of the result in late 1991. On return trip to Sarawak in March 1992, it was found that the tree had been cut down by local people most likely for fuel and building material. There was no other trees of the same variety existed in the Lundu region. The collectors then returned home with samples from other varieties of the Calophyllum lanigerum species, most of which failed to show any anti-HIV properties. Then, a few existing species were eventually located in the Singapore Botanic Gardens. With sufficient raw materials, the scientists were able to isolate the active ingredient as -Calanolide A. Since the plant source is relatively rare, a method of total synthesis was developed in 1996 which showed same effectiveness against HIV virus when compared to the original compound. In addition, the samples collected from the trip in March 1992 yielded another positive result. A sister compound -Calanolide B was isolated from the latex of Calophyllum teysmannii var. innophylloide trees. Sarawak Forestry Department was in collaboration with University of Illinois at Chicago for sustainable harvest of -Calanolide B. Although Costatolide is less potent than Calanolide A, the yield from raw materials is much higher when compared to Calanolide A. Therefore, Costatolide had been accepted as replacement for Calanolide A. In June 1993, The Calophyllum Species Order was issued by the Sarawak state government to ensure adequate supply of the trees for medicinal purposes. In the same year, International Convention on Biological Diversity treaty came into effect with 179 countries as its signatories. However, the United States did not sign the treaty. Therefore, the Sarawak state government set up Sarawak Biodiversity Centre in 1997 to regulate bioprospecting activities in the state. In 1994, NCI signed a "letter of collection" with Sarawak state government. NCI also partnered with a small American pharmaceutical company named MediChem Research Inc based in Lemont, Illinois to develop the Calanolide compound. In 1995, NCI granted MediChem all rights to develop the compound. Due to lack of funds, Medichem entered a joint venture with Sarawak state government in 1996 where the former provided technical expertise and facilities for Sarawak scientists. Meanwhile, the state government provided further funding for the development of the compound. Sarawak MediChem pharmaceuticals company was then created as a result of the joint venture. Both partners have 50:50 percent stake in all intellectual property rights of the venture. In December 2006, Craun Research Sdn Bhd, a company established by the Sarawak state government in 1993, acquired Sarawak MediChem Pharmaceuticals. In 2016, Craun Research announced the successful completion of Phase I trial of the drug. In 2019, Dr Annuar Rapaee, Sarawak Assistant Minister for Education, Science and Technological Research admitted the slow progress in developing and commercialising the drug.
Mechanism of action
Calanolide A is unique among non-nucleoside reverse transcriptase inhibitor in that it may bind two distinct sites in reverse transcriptase, namely active site and Foscarnetbinding site of the enzyme. The drug also acts in synergistic fashion with nevirapine in inhibiting HIV-1 virus. In 2003, the Calanolide A compound was found to have anti-tuberculosis activity. F18, a structural analog of Calanolide A was derived in 2017 which could have more potent anti-HIV activity than original molecule.
Side effects
Calanolide A has a relatively good safety profile. A Phase I clinical trial done in 2001 on 47 healthy subjects showed that the side effects were taste alteration, headache, belching, and nausea.
