Important note: Information in this article was accurate in May 2001. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, May 7, 2001
Michael Greer, Staff Medical Writer
NewsRx - Researchers in France say that a derivative of the antiretroviral HIV drug zidovudine, better known as AZT, is many times more powerful than the original.
"Prodrugs of [AZT] have been synthesized in an effort to enhance its uptake by HIV-1 infected cells and its anti-HIV activity," P. Vlieghe and colleagues explained in the Journal of Medicinal Chemistry.
AZT analogs with a 5'-O-carbonate moiety exhibited surprisingly potent inhibition of HIV replication, they found.
One aspect of the 5'-O-carbonate prodrugs that caught the eye of Vlieghe's group was the manner of their creation. Unlike AZT analogs with other moieties, including 5'-O-carbamate and 5'-O-ester, 5'-O-carbonate derivatives underwent rearrangement via an intramolecular cyclic process during enzymatic hydrolysis, they said.
One 5'-O-carbonate analog, dubbed "compound 10," displayed particularly robust antiviral activity. The 50% effective concentration (EC50) of this AZT prodrug was 0.78 nM against infected peripheral blood mononuclear cells, and dropped to 0.5 nM for infected MT-4 cells, study data showed.
These results indicated that compound 10 was up to 50 times as powerful as normal AZT ("New 3 '-azido-3 '-deoxythymidin-5 '-yl O-(Omega-hydroxyalkyl) carbonate prodrugs: Synthesis and anti-HIV evaluation," J Med Chem 2001 Mar 1;44(5):777-86.
"Our results suggest that the specific intramolecular rearrangement associated with the [5'-O-carbonate] prodrugs could explain the remarkable anti-HIV-1 activity of this series of AZT prodrugs," Vlieghe and colleagues concluded. "Prodrug 10 may...have better clinical potential than AZT for the treatment of AIDS."
The corresponding author for this report is J.L. Kraus, Luminy Science Faculty, Laboratory for Biomolecular Chemistry, 163 Avenue Luminy, Case 901, F-13288 Marseille 9, France.
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Key points reported in this study include:
This article was prepared by AIDS Weekly editors from staff and other reports.
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