Mr. Mayur S. Jain*, Dr. Shashikant D. Barhate, Mr. Bhushan P. Gayakwad
Shree Sureshadada Jain Institutes of Pharmaceutical Education and Research, Jammer, Maharashtra (India).
Calanolide A is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) derived from a plant found in the Malaysian rain forest. A related compound, calanolide B, also has anti-HIV activity. Both drugs are being developed by Sarawak Pharmaceuticals. A preliminary dosing study among HIV-infected individuals showed a significant antiviral effect compared with placebo. Calanolide A is a compound isolated from the latex of the tree, Calophyllum lanigerum (var. austrocoriaceum), that grows in the rain forest of the Malaysian state of Sarawak on the island of Borneo.
Calanolide A is an experimental non-nucleoside reverse transcriptase inhibitor (NNRTI) first acquired from the Calophyllum lanigerum,variety austrocoriaceum, trees in the Malaysian state of Sarawak by botanist John Burley in 1987. The U.S. National Cancer Institute tested calanolide A as a possible cancer treatment, but had no effect. It was later found to have potent anti-HIV activity.1,2 On return trip to Malaysia, it was found that all of the austrocoriaceum variety tree species of Calophyllum lanigerum had been cut down most likely for fuel and building material in the swamp forest near Lundu where the first tree samples were taken; however, a few existing species were eventually located in the Singapore Botanic Gardens. Since the plant source is relatively rare, a total synthesis was developed in 1996. The form in current use is formulated for oral administration and produced by Sarawak MediChem in Lemont, Illinois.
Calanolide A is unique among NNRTIs in that it may bind two distinct sites in reverse transcriptase.3,4
Chemical formula: C22H26O5
Molecular weight: 370.445 g/mol
Metabolism is primarily taken place by hepatic enzymes.
For use in combination treatment of HIV infection (AIDS).
Mechanism of action:
Viral life-cycle studies indicate that calanolide A acts early in the infection process, similar to the known HIV reverse transcriptase (RT) inhibitor 2', 3'-dideoxycytidine. In enzyme inhibition assays, calanolide A potently and selectively inhibits recombinant HIV type 1 RT but not cellular DNA polymerases or HIV type 2 RT within the concentration range tested.3,4
Half life (t50%): 20 hours for 800mg
Calanolide A is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) derived from a plant found in the Malaysian rain forest. A related compound, calanolide B, also has anti-HIV activity. Both drugs are being developed by Sarawak Pharmaceuticals. The drug is metabolised by cytochrome P450 CYP3A, and its developers have suggested that drug levels may be enhanced if co-administered with ritonavir (Norvir). The drug is active in the test tube against HIV with the two most common NNRTI-related mutations, K103N and Y181C, and selects for a mutation which does not cause cross-resistance with any other NNRTIs currently under investigation. A substitution at codon Y188H of reverse transcriptase has been associated with 30-fold resistance to calanolide A in vitro (Quan 1999). The compound is essentially inactive against strains of the less common HIV type 23,4
Initial studies show promise for treating HIV-1
Calanolide A is a compound isolated from the latex of the tree, Calophyllum lanigerum var. austrocoriaceum , that grows in the rain forest of the Malaysian state of Sarawak on the island of Borneo. There are at least 200 species in the genus Calophyllum .
Calanolide A is an investigational anti-HIV drug. Its safety and efficacy remain to be defined.
Calanolide A is an investigational anti-HIV drug that has been given in early clinical trials at an oral dose of 200 to 800 mg; however, it is not available for use. Its safety and efficacy remain to be defined.
Information regarding safety and efficacy in pregnancy and lactation is lacking.1,2
This recently discovered natural product has been found to specifically inhibit the DNA polymerase activity of HIV-1 RT, but not HIV-2 RT. This information warrants further investigation in human clinical trials. Calanolide A has been found to inhibit a wide variety of HIV-1 strains, drug-resistant strains, and HIV disease in various stages. Calanolide A appears to act early in the infection process similar to dideoxycytidine. Calanolide A's complex biochemical mechanism of inhibition has suggested the presence of 2 binding sites, 1 competitive, 1 noncompetitive. Calanolide A binds near the active site of the enzyme and interferes with deoxynucleotide triphosphate binding. Many RT inhibitors bind to a common site on HIV-1 RT; whereas calanolide A may bind to a different site or sites on the enzyme. Changes in the nonnucleoside inhibitor binding site itself may also alter effects. One report discusses cross-resistance of certain viral strains. Single mutations at certain amino acids can yield virus with either higher or lower resistance.
The authors would like to thanks Shree. Sureshadada Jain Institutes of Pharmaceutical Education and Research, Jamner Maharashtra (India) for supporting the fulfillment of this work.
CONFLICT OF INTEREST:
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3. Flavin MT, Rizzo JD, Khilevich A, et al. (1996). "Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (±)-calanolide A and its enantiomers". J Med Chem. 39 (6): 1303–13.
4. Creagh T, Ruckle JL, Tolbert DT, et al. Safety and pharmacokinetics of single doses of (+)-calanolide a, a novel, naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy, human immunodeficiency virus-negative human subjects. Antimicrob Agents Chemother. 2001; 45:1379-1386.
5. Shenon P. Hunt in forests of Borneo aims to track down natural drugs. New York Times. 1994 Dec 6.
6. Eiznhamer DA, Creagh T, Ruckle JL, Tolbert DT, Giltner J, Dutta B, Flavin MT, Jenta T, Xu ZQ: Safety and pharmacokinetic profile of multiple escalating doses of (±)-calanolide A, a naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy HIV-negative volunteers. HIV Clin Trials. 2002 Nov-Dec; 3(6):435-50. [PubMed: 12501127]
7. Xu ZQ, Barrow WW, Suling WJ, Westbrook L, Barrow E, Lin YM, Flavin MT: Anti-HIV natural product (±)-calanolide A is active against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis. Bioorg Med Chem. 2004 Mar 1; 12(5):1199-207. [PubMed:14980631]
8. Currens MJ, Mariner JM, McMahon JB, Boyd MR (1996). "Kinetic analysis of inhibition of human immunodeficiency virus type-1 reverse transcriptase by calanolide A". J Pharmacol Exp Ther. 279 (2): 652–61. PMID 8930168.
Received on 22.05.2018 Accepted on 05.09.2018
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Asian J. Pharm. Res. 2018; 8(4): 241-242.