Laurent Bellon

Pharmacokinetics and tolerability of an antiangiogenic ribozyme (ANGIOZYME) in healthy volunteers

The pharmacokinetics and tolerability of a chemically stabilized synthetic ribozyme (ANGIOZYME™) targeting the Flt‐1 VEGF receptor mRNA were evaluated in healthy volunteers. In a placebo‐controlled, single‐dose escalation study, ribozyme was administered as a 4‐hour IV infusion of 10 or 30 mg/m2 or as a SC bolus of 20 mg/m2. Peak ribozyme plasma concentrations of 1.5 and 3.8 μg/mL were observed after the 10 and 30 mg/m2 IV infusions, respectively. When normalized to dose, AUC values as well as peak concentrations increased proportionally as the dose was increased from 10 to 30 mg/m2. Peak concentrations of 0.9 μg/mL were observed approximately 3.25 hours after a 20 mg/m2 SC bolus of ribozyme. The dose‐normalized AUCs obtained after SC dosing were compared to the mean dose‐normalized AUC after IV dosing to estimate an absolute SC bioavailability (f) of approximately 69%. An average elimination half‐life of 28 to 40 minutes was observed after IV administration, which increased to 209 minutes after SC administration. Only 4 of 12 reported adverse events were possibly related to administration of ribozyme (headache and somnolence). Thus, ribozyme administration was well tolerated after a single 4‐hour IV infusion of up to 30 mg/m2 or a single SC bolus of 20 mg/m2.

Efficient Synthesis of 4-Thio-D-ribofuranose and Some 4′-Thioribonucleosides

Abstract A synthetic pathway to reach easily the 4-thio-D-ribofuranose is described. Some corresponding pyrimidine α and β 4′-thioribonucleosides have been synthesized and evaluated as antiviral agents against various viruses.

Amino-Linked Ribozymes: Post-Synthetic Conjugation of Half-Ribozymes

Abstract A convergent approach, based on the reductive amination of 3′-phospho-glycaldehyde-ribozyme 3 with 5′-aminohexyLribozyme 1 generated an amino-linked ribozyme 4 in good yields. Catalytic activity of the cross-linked ribozyme is discussed.

4′-Thio-β-D-oligoribonucleotides: Nuclease Resistance and Hydrogen Bonding Properties

Abstract The syntheses and the study of nuclease resistance and hydrogen bonding of modified oligoribonucleotides, i.e. 4′-thio-β-D-oligoribonucleotides (4′-S-RNA), are reported.

A reinvestigation of the synthesis of 4-thio-pentofuranosides for further nucleosidic synthesis

Abstract We demonstrate that the procedure of Huang and Hui(4), applied to the D-ribose and involving Ph3P/I2/Imidazole reagent system do not lead to the desired 4-thio-D-ribofuranoside derivative but gives its diastereoisomer 4-thio-L-lyxofuranoside derivative 4