Jenta T, Soejarto D, Buckheit R, Arnold E, Schweikart K, Covey J; Conference on Retroviruses and Opportunistic Infections.
Program Abstr 6th Conf Retrovir Oppor Infect Conf Retrovir Oppor Infect 6th 1999 Chic Ill. 1999 Jan 31-Feb 4; 6th: 180 (abstract no. 602).
Sarawak MediChem Pharmaceuticals, Lemont, IL.
(-)-Calanolide B, a naturally-occurring non-nucleoside reverse transcriptase inhibitor (NNRTI), can be easily purified in reasonable yield (30-40%) from the latex of Calophyllum teysmannii var. inophylloide, a tropical rainforest tree indigenous to Sarawak, Malaysia. Recent field studies have shown that controlled harvesting of the tree latex provides a non-destructive and sustainable source for (-)-calanolide B. The activity (EC50) of (-)-calanolide B towards laboratory and clinical strains of HIV-1 in fresh and established human cells ranged from 0.03 to 0.80 micromolar. Furthermore, synergistic interactions with nucleoside analogues and other NNRTIs were observed during in vitro drug combination studies, with synergy volumes ranging from 100 to 500 micromolar (2)%. In addition, crystal structures of calanolide analogues complexed to HIV-1 RT suggest a common mode of association to the NNRTI binding pocket. Due to the relative planarity of the calanolide fused-ring system, binding of the calanolide inhibitors is unique and exhibits distinct differences to the binding models of other NNRTIs. In particular, the potential for an additional hydrogen bond extending from the Cys181 side chain to the bound calanolide inhibitor may account for the enhanced susceptibility of the NNRTI-resistant Tyr181Cys mutant to inhibition by calanolide compounds. In conclusion, the antiviral properties of (-)-calanolide B, coupled with its ready availability from a replenishable natural source, make it a good anti-HIV drug candidate for further evaluation and preliminary animal toxicology and pharmacokinetic studies are now underway.
Publication Types:
Keywords:
- Anti-HIV Agents
- Antiviral Agents
- Coumarins
- HIV-1
- Humans
- In Vitro
- Malaysia
- Pyranocoumarins
- Reverse Transcriptase Inhibitors
- calanolide B
- reverse transcriptase, Human immunodeficiency virus 1
Other ID:
UI: 102195367
From Meeting Abstracts