Important note: Information in this article was accurate in August 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, August 23, 1999
Daniel J. DeNoon, Senior Editor
CW HENDERSON PUBLISHER -- A new member of a potent class of HIV drugs is active against viral strains resistant to other members of the class.
The new nonnucleoside reverse transcriptase inhibitor (NNRTI) is costatolide, the isomer of calanolide A previously known as (-)-calanolide B. New studies show that it is active against HIV with the Y181C point mutation that confers resistance to most NNRTIs.
This means that costatolide could be combined with a different NNRTI. Such a combination would require a third drug such as a nucleoside-analog reverse transcriptase inhibitor (NARTI) to ensure against rapid development of resistant HIV.
"The possibility of using two NNRTIs in a cocktail with a third NARTI may be clinically useful from the viewpoint of preserving the possibility of using more potent future therapies with the protease inhibitors," suggested Robert W. Buckheit of the Southern Research Institute, Frederick, Maryland, and colleagues.
Buckheit et al. reported their findings in the Journal Antimicrobial Agents and Chemotherapy ("Unique Anti-Human Immunodeficiency Virus Activities of the Nonnucleoside Reverse Transcriptase Inhibitors Calanolide A, Costatolide, and Dihydrocostatolide," Antimic Ag Chem, 1999;43(8):1827-34).
Noting that (+)-calanolide A was a unique NNRTI, Buckheit et al. explored the antiviral properties of two of its isomers, costatolide and (-)-dihydrocalanolide B (dihydrocostatolide).
Both of these calanolide analogs had 10-fold enhanced activity against Y181C mutant HIV strains. The drugs were even more potent against HIV strains with both the Y181C NNRTI-resistance mutation and mutations conferring resistance to zidovudine (AZT).
Both drugs had somewhat reduced activity against HIV strains with other NNRTI-resistance mutations, but costatolide had the smallest loss of activity.
Combination of costatolide with other anti-HIV drugs resulted in synergistic inhibition of the virus.
HIV resistant to calanolide A exhibited a previously unreported NNRTI resistance mutation, T139I. Costatolide remained active against HIV bearing this mutation, but the additional L100I mutation conferred costatolide resistance. HIV with both the T139I and L100I mutations was resistant to most NNRTIs but not to (alpha)-APA, which retained full activity.
"Our results demonstrate that the calanolide isomers can be clearly distinguished from other members of the NNRTI class, and thus, that the compounds may be useful in combination with other anti-HIV agents," Buckheit et al. wrote.
This work was supported by a contract from the National Cancer Institute.
The corresponding author for this study is Robert W. Buckheit Jr., Infectious Disease Research Department, Serquest/Southern Research Institute, 431 Aviation Way, Frederick, Maryland 21701. Phone: (301) 694-3232, ext. 127. Fax: (301) 694-7223. Email: <buckheit@sri.org>.
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