XU Z, BUCKHEIT RW, HOLLINGSHEAD MG, FLAVIN MT; Interscience Conference on Antimicrobial Agents and Chemotherapy.

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 1999 Sep 26-29; 39: 315 (abstract no. 921).

Sarawak MediChem Pharmaceuticals, Inc., Lemont, IL

BACKGROUND: (+)-Calanolide A, originally isolated from several tropical plants of the genus Calophyllum in Malaysia, demonstrated activity against HIV-1. It was selected for further pharmacological and clinical development.METHOD: (+)-Calanolide A has been studied in the in vitro assays for range of activity against HIV, cross-resistant profile and effect of combination with other anti-HIV agents. In addition, the in vivo anti-HIV efficacy of (+)-calanolide A has been evaluated in the hollow fiber-based mouse model.RESULTS: (+)-Calanolide A was active against a wide range of laboratory and clinical isolates of HIV-1 in a series of established and fresh human cell lines. (+)-Calanolide A exhibited an enhanced activity against isolates with a Y181C mutation as well as isolates containing Y181C and AZT-resistant mutations; it was active against virus isolates with dual mutations of Y181C and K103N, which are the two most common mutations conferring resistance to NNRTIs. Synergistic effect was observed in vitro for the combination of (+)-calanolide A with nucleoside analogues, protease inhibitors, and other NNRTIs. A significant anti-HIV activity of (+)-calanolide A was shown in the hollow fiber mouse study. Following oral or parenteral administration on a once- or twice- daily treatment schedule, (+)-calanolide A was capable of completely suppressing virus replication in two distinct and separate physiologic compartments (peritoneal cavity and subcutaneous site). Furthermore, a synergistic effect was observed for the combination of (+)-calanolide A and AZT in this animal model.CONCLUSION: The in vivo efficacy demonstrated here, along with a variety of in vitro studies, suggests that (+)-calanolide A has characteristics favorable for its development as a clinical candidate against AIDS.

Publication Types:

• Meeting Abstracts

Keywords:

• Acquired Immunodeficiency Syndrome
• Animals
• Anti-HIV Agents
• HIV Infections
• HIV Seropositivity
• HIV-1
• Humans
• In Vitro
• Malaysia
• Mice
• Mutation
• Pyranocoumarins
• Virus Replication
• Zidovudine
• genetics
• reverse transcriptase, Human immunodeficiency virus 1
• virology

Other ID:

• GWAIDS0009039

UI: 102246536

From Meeting Abstracts