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Calanolide A: How it works?

Calanolide A: How it works?

What is Calanolide A?

Calanolide A is an investigational antiretroviral agent under the drug class non-nucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of HIV infection. The compound is isolated from the plant species Calophyllum lanigerum, austrocoriaceum variety, locally known as Bintangor tree. The World Health Organization (WHO) has issued a memorandum, suggesting that ethnomedicines and other natural products should be tested against HIV, as they can be an effective and more affordable source of therapeutic antiretroviral agents. As a result, various naturally-occurring compounds have been proposed as promising ingredients for anti-HIV medications, mainly natural products that act against viral enzymes reverse transcriptase, protease, and integrase. Calanolide A is one of these compounds.

How Calanolide A works

In laboratory research, it was found that Calanolide A acted early in the infection process, just like the known reverse transcriptase inhibitor- 2’,3’-dideoxycytidine. Enzyme inhibition assays revealed that the compound effectively inhibited recombinant HIV-1 reverse transcriptase but not DNA polymerases or HIV-2 reverse transcriptase. Calanolide A also exhibited enhanced antiviral activity against drug-resistant strains. Viruses containing Y181C and K103N dual mutations are highly resistant to all approved NNRTIs, including efavirenz, delavirdine, and nevirapine. But, when Calanolide compounds were challenged with viruses containing dual mutation, the compounds remained active.

In animal models and cultured cells, calanolide demonstrated synergistic effects when combined with other antiretroviral agents. When the infected host cells were exposed to increasing concentrations of calanolide A in serial passages, resistant strains were created. Calanolide A failed to inhibit reverse transcriptase from these resistant strains, but they have shown sensitivity to other NNRTIs and NRTIs, including nevirapine and 3'-azido-2',3'-dideoxythymidine triphosphate (zidovudine). Calanolide possesses a unique quality among conventional NNRTIs, as it showed potential ability to bind to two distinct sites in reverse transcriptase: the active site and the Foscarnet binding site. The drug also has synergistic effects with nevirapine in inhibiting HIV type 1 virus.       

What conditions are treated with Calanolide A?

Calanolide A has been identified as an excellent addition to the NNRTI family in treating HIV infection, particularly resistant virus strains. Unlike other antiretroviral agents from this class, calanolide compound has been postulated to bind to the HIV reverse transcriptase active site, competing with deoxynucleoside triphosphate. In Phase I studies, the novel NNRTI was well tolerated. Calanolide A has potential clinical applications in combination with other potent antiretroviral drugs in suppressing viral mutations. Being an experimental drug, the oral dose given to subjects were 200–800mg but is not yet available for clinical use.

When will Calanolide A be available in the market?2

The investigational drug is currently in clinical trials and is not yet approved by the FDA for clinical use.

Due to the scarcity of the plant source, a related species Calophyllum teysmannii (var. inophylloide) was also used to isolate a compound called Castatolide, which also exhibited anti-HIV activity. The compound is now known as Calanolide B. The new compound is currently in preclinical testing with the National Cancer Institute. In 2016, Craun Research announced that Phase I clinical trials for Calanolide A have been completed. The next steps will be to conduct a market survey and out-licensing exercises for the compound.

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