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Alkylglycerol Foscarnet Analogs Are Active In Vitro at Submicromolar Concentrations against a Panel of Drug-Resistant Strains of HIV-1 K. Y. HOSTETLER*1, J. R. BEADLE1, S. E. HOSTETLER1, G. D. KINI1, K. A. ALDERN1, D. D. RICHMAN1, J. L. HAMMOND2, D. L. ZONARICH2, H. Z. BAZMI2, and J. W. MELLORS2. 1VA Med. Ctr. and Univ. of California, San Diego, La Jolla; and 2VA Med. Ctr. and Univ. of Pittsburgh, PA Alkylglycerol analogs of foscarnet (PFA) have substantially greater antiviral activity than PFA in vitro. The batyl alcohol analog of PFA (1-O-octa- decyl-glycero-3-PFA, B-PFA) has an EC50 of 1.4 mM versus 16.3 mM for PFA against HIV-1LAI in MT-2 cells. The 2-methyl and 2-ethyl substituted analogs, MB-PFA and EB-PFA, are even more potent with EC50 values of 0.28 and 0.39 mM. Selectivity indices for MB-PFA and EB-PFA are 950 and 1900. In plaque reduction assays in HT4-6C cells infected with HIV-1LAI, MB-PFA was highly synergistic with AZT in vitro with combination index values as low as 0.14 at the EC90. Preliminary studies in mice indicate that alkylglycerol-PFA analogs are well absorbed orally. We evaluated the antiviral activity of MB-PFA and EB-PFA against a panel of drug resistant strains of HIV-1 including those resistant to AZT, 3TC, dideoxynucleosides and NNRTIs in MT-2 cells by inhibition of p24 production. EB-PFA and MB-PFA were both highly active against strains resistant to AZT, 3TC, AZT+3TC, ddNs and NNRTIs with EC50 values ranging from 0.32 to 1.34 mM (EB-PFA) and 0.13 to 0.97 mM (MB-PFA). EB-PFA and MB-PFA were somewhat less active against a strain encoding K65R with EC50 values of 3.22 and 1.24 mM versus 57.3 mM for PFA. In summary, EB-PFA and MB-PFA exhibited excellent antiviral activity against a panel of drug resistant strains of HIV-1. These compounds should be evaluated further as a potential salvage therapy in patients with drug resistant HIV-1 strains. Key Words: foscarnet, HIV drug resistance, prodrugs |
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© 7th
Conference on Retroviruses and Opportunistic Infections, |