Giuseppe Gumina

L - Nucleosides: Antiviral Activity and Molecular Mechanism

Drug discovery for antiviral chemotherapy has provided the effective treatment of numerous viral diseases. Among antiviral agents used in therapy, nucleoside analogues have been particularly useful. In fact, almost twenty nucleosides are currently used in antiviral therapy, seven of which are for the treatment of HIV infection. In the search for new and effective agents within this class, the focus has recently expanded on L-analogues, characterized by opposite configuration compared to the natural D-nucleosides. The interest in L-nucleosides has risen since the discovery of 3TC, one of the most important drugs used in the treatment of AIDS and hepatitis B infection. This review will discuss the latest advances in L-nucleosides as antiviral agents with a particular focus on the synthesis and molecular mechanism as well as metabolic differences between L- and D-nucleosides.

Pharmacokinetics of the Antiviral Agent β-l-3′-Fluoro-2′,3′-Didehydro-2′,3′-Dideoxycytidine in Rhesus Monkeys

ABSTRACT β-l-3′-Fluoro-2′,3′-didehydro-2′,3′-dideoxycytidine (l-3′-Fd4C) is a potent and selective antiretroviral nucleoside with activity against lamivudine-resistant human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV) in vitro. The pharmacokinetics of l-3′-Fd4C were characterized in three rhesus monkeys given single intravenous and oral doses. A two-compartment open model was fitted to the plasma and urine data. Plasma concentrations declined in a biexponential fashion with an average beta half-life of 12.45 h and central and steady-state volumes of distribution of 0.43 and 1.90 liters/kg, respectively. The average systemic and renal clearance values were 0.23 and 0.08 liters/kg, respectively, and the apparent mean terminal half-life of the oral dose was 12.5 h. The serum concentrations exceeded the 90% effective concentration value for lamivudine-resistant and wild-type HIV-1 after oral administrations. A large variation was observed in the oral bioavailability, which ranged from 15 to 31%. To determine whether the bioavailability may be improved by using a basic buffer solution, the oral dose was repeated to the same animals in a sodium bicarbonate solution. The bioavailability of l-3′-Fd4C administered with sodium bicarbonate was not significantly different from the bioavailability when the oral dose was administered in the absence of buffer (P = 0.49), suggesting that further development of this compound may warrant other approaches, such as development of a prodrug to improve its oral absorption.