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3rd International Workshop on HIV Drug Resistance2-5 August 1994, Kauai, Hawaii, USA |
IN VITRO EVALUATION OF N-α-ACETYL-NONA-D-ARGININE (ALX40-4C): ANTIVIRAL EFFICACY AND EMERGENCE OF RESISTANCE
Int Wkshop HIV Drug Res 1994 Aug 2-5;3:44 (abstract no. 43)
B. Conway1, O. Mpanju1 , Y. Zheni2, S.C. Climie2 and M. Sumner-Smith2
lUniversity of British Columbia, Vancouver, British Columbia, Canada, and 2Allelix Biopharmceuticals Inc., Mississauga, Ontario, Canada
N-α-acetyl-nona-D-arginine (ALX40-4C) has been developed as a competitive antagonis of HIV-1 Tat binding to TAR. We have evaluated its antiretroviral activity in vitro. In an acute infection model, comprised of mononuclear cells (MCs) infected with HTLV-IIIB (MOI=0.143), we demonstrated an IC50= 1-2 µM. Repeat experiments at MOI=0.001 showed IC50 < 0.1 µM. We then evaluated drug activity against clinical isolates (H112-2 and G910-6) at MOI=0.01. For H112-2, we found 5 µM<IC50 < 20 µM, although synergistic activity between 100 nM ZDV/5 µM ALX40-4C was observed. For G910-6, we showed IC50 < 5 µM. In experiments to evaluate the development of resistance to ALX40-4C, HTLV-IIIB was grown in target cells with progressively increasing drug concentrations (0.5, 1, 2 µM) over 84 days. Viral stocks (> 105 TCID 50/ml) were thus generated, and are currently being evaluated for susceptibility to ALX40-4C.
The drug has demonstrated activity against herpes viridae, including HSV-1, by a mechanism that likely involves inhibition of a viral uptake step. The potential for development of drug resistance was assessed by culturing HSV-1 (strain F) in VERO cells under conditions of increasing drug concentration. Plaque purified stocks were prepared and reassessed for their sensitivity to ALX40-4C. Preliminary results suggest that partial resistance was induced. ALX40-4C is a promising antiviral compound with activity against HIV-1, as well as opportunistic AIDS viral pathogens. Our preliminary evaluations suggest that as with most current antiviral agents, viral drug-resistance may emerge under selection. Thus, it will be important to watch carefully for the emergence of resistance in the clinical trials of the drug which are currently underway.
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1994-08-02
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