[19] D-FDOC: A DIOXOLANE PYRIMIDINE NUCLEOSIDE WITH ACTIVITY AGAINST COMMON NUCLEOSIDE-RESISTANT HIV-1

XI International HIV Drug Resistance Workshop: Basic Principles and Clinical Implications

Seville, Spain, 2–5 July 2002

D-FDOC: A DIOXOLANE PYRIMIDINE NUCLEOSIDE WITH ACTIVITY AGAINST COMMON NUCLEOSIDE-RESISTANT HIV-1

Antivir Ther. 2002;7(Suppl 1):S15 (abstract no. 19)

RF Schinazi¹, J Mellors², S Erickson–Viitanen⁴, J Mathew¹, U Parikh2, P Sharma¹, M Otto⁴, Z Yang³, CK Chu³ and DC Liotta¹
¹Emory University/VA Medical Center, Atlanta, Ga., USA, ²University of Pittsburgh, Pittsburgh, Pa., USA; ³The University of Georgia, Athens, Ga., USA; and ⁴Pharmasset Inc, Tucker, Ga., USA

Molecular modelling studies predict that the dioxolane moiety of D-nucleoside analogues does not sterically clash with Val184 in M184V mutant reverse transcriptse (RT) and has stabilizing interactions with substrate binding residues such as Tyr115 and Arg72 that could preserve activity against zidovudine- or lamivudine- resistant HIV-1. This prompted us to evaluate β-D- 5-fluoro-dioxolane-cytosine (D-FDOC) as a potential agent against nucleoside resistant viruses. D-FDOC is an effective inhibitor of HIV-1, HIV-2, SIV, and hepatitis (HBV) in vitro. EC₅₀ and EC₉₀ values in primary human lymphocytes infected with HIV-1LAI were 0.04 and 0.26 μM, respectively. Molecular infectious clones containing M184V or M41L/D67N/K70R/T215Y/ K219Q were as susceptible as wild-type virus (WT-pNL4-3) to D-FDOC. As expected, L-FDOC was essentially inactive against the M184V variant. Using HIV-1 containing the K65R mutation, a fourfold increase in EC₅₀ was noted with D-FDOC in human peripheral blood mononuclear cells. Its triphosphate (D-FDOC-TP) inhibited HIV-1 RT with an IC₅₀ of 0.004 μM. D-FDOC-TP was significantly less inhibitory than ddCTP against γ DNA pol. Its intracellular half-life in MT-2 cells was comparable to D-D4FC (≥18 h), a related nucleoside currently in Phase I clinical trials. In primary mouse bone marrow cells, D-FDOC showed no increase in lactic acid production even at 300 μM. In contrast, treatment with L-FDOC and ddC resulted in a >300 % increase in lactic acid relative to untreated control. In Swiss mice treated for 5 days at 3.3 to 100 mg/kg (once-a-day, intraperitoneally), no overt toxicity was apparent at any dose. Taken together, the potent and selective activity of D-FDOC against M184V and zidovudine-resistant HIV-1 variants suggest that advanced pharmacological and toxicological studies of this compound should be pursued.

(Supported by the Department of Veterans Affairs and NIH grants).

PRESENTING AUTHOR: RF Schinazi

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2002-07-02
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