Stavudine Analogue TKD-114 Boosts Anti-HIV Activity in vitro

An altered version of stavudine shows reduced cytotoxicity and increased action against HIV-1, researchers report in the May issue of Antimicrobial Agents and Chemotherapy.

The use of stavudine, also known as D4T, is limited by long-term delayed peripheral sensory neuropathy related to mitochondrial damage, Dr. Yung-Chi Cheng of Yale University, New Haven, Connecticut and colleagues note.

To investigate whether structural manipulation of the drug might reduce these effects, the researchers synthesized and screened a number of 4'- substituted D4T analogues, including 4'-ethynyl D4T.

The 4'-ethynyl D4T variant exhibited less mitochondrial and cellular toxicity than D4T, and its antiviral effect was five times greater.

In other studies it was found to act synergistically with lamivudine and elvucitabine. With didanosine and zidovudine, its action was additive.

D4T is broken down by the catabolic enzyme phosphorylase, the researchers note. However, the level of breakdown of 4'- ethynyl DVT was below the threshold of detection.

"The agent, now known as TKD-114, has shown other advantages in unpublished studies," Dr. Yung-Chi Chen told Reuters Health, and its use as a key drug in future antiretroviral regimens should be explored.

06/04/04

Antimicrob Agents Chemother 2004;48:1640-1646.