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1st International Workshop on HIV Drug Resistance & Treatment Strategies25-28 June 1997, St. Petersburg, Florida, USA |
UNIQUE ANTI-HIV PROPERTIES OF THE CALANOLIDE A ANALOGUES COSTATOLIDE AND DIHYDROCOSTATOLIDE
Antiviral Therapy 1997;2 (Suppl 5):5 (abstract no. 8)
TL Stup, EL White, V Fliakas-Boltz, A Weigand, MC Osterling and RW Buckheit Jr
Southern Research Institute, Frederick, Maryland, USA
The non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI) calanolide A has been previously reported as a unique and specific inhibitor of HIV-1. Two isomers of (+)-calanolide A are described which possess antiviral properties similar to those of calanolide A. These compounds, (-)-calanolide B (costatolide) and (-)-dihydrocalanolide B (dihydrocostatolide), possess all of the phenotypic properties ascribed to the pharmacological class of NNRTIs. Unlike other NNRTIs, the calanolides exhibit 10-fold enhanced antiviral activity when challenged with drug-resistant viruses bearing the Y181C amino acid change in the RT. Furthermore, mechanistic evaluation of the inhibition of RT by costatolide and dihydrocostatolide indicates that the compounds inhibit RT by a complex mechanism. At low concentrations (<0.2 µM) the inhibition of RT exhibits a mixed type in which the inhibitor affects both the Km and Vmax of the enzyme. At higher concentrations, a second mode of inhibition appears. Similar to calanolide A, loss of activity of the isomers was observed against virus isolates and RT with amino acid changes at residues 100, 103, 139 and 188 in the RT. When compared directly with calanolide A, costatolide exhibited a relatively smaller loss of activity against many of these NNRTI-resistant viruses. Comparison of cross-resistance data using a panel of NNRTI-resistant virus isolates suggests that each of the stereoisomers may interact differently with the RT despite their high degree of structural similarity. Combination studies were performed to determine the effects of combining costatolide and dihydrocostatolide with other NNRTIs with regard to anti-HIV efficacy and resistance selection. The compounds selected for a variety of amino acid changes depending on the cell line used for selection (L100I, T139I, L187F and Y188H) and on the compound chosen for use in combination. In conclusion, cross-resistance and resistance selection comparisons indicate that the calanolides represent a novel and distinct subgroup of the NNRTI family. Our preclinical evaluations suggest the possible therapeutic benefit of using the calanolide A analogues in combination with other anti-HIV agents. They may be most useful in patients which have been previously exposed to NNRTIs, based on the ability of the analogues to inhibit viruses with many of the commonly occurring NNRTI-resistant amino acid changes.
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1997-06-25
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