THE BOTTLENECK IN AZT ACTIVATION

Citation
A. Lavie et al., THE BOTTLENECK IN AZT ACTIVATION, Nature medicine, 3(8), 1997, pp. 922-924
Citations number
16
Categorie Soggetti
Medicine, Research & Experimental",Biology,"Cell Biology
Journal title
ISSN journal
10788956
Volume
3
Issue
8
Year of publication
1997
Pages
922 - 924
Database
ISI
SICI code
1078-8956(1997)3:8<922:TBIAA>2.0.ZU;2-P
Abstract
Nucleoside-based inhibitors of reverse transcriptase were the first dr ugs to be used in the chemotherapy of AIDS. After entering the cell, t hese substances are activated to their triphosphate form by cellular k inases, after which they are potent chain terminators for the growing viral DNA (ref. 1). The two main factors limiting their efficacy are p robably interrelated. These are the insufficient degree of reduction o f viral load at the commencement of treatment and the emergence of res istant variants of the virus. The reason for the relatively poor suppr ession of viral replication appears to be inefficient metabolic activa tion. Thus, for the most extensively used drug, 3'-azido-3'-deoxythymi dine (AZT), whereas phosphorylation to the monophosphate is facile, th e product is a very poor substrate for the next kinase in the cascade, thymidylate kinase(2,3). Because of this, although high concentration s of the monophosphate can be reached in the cell, the achievable conc entration of the active triphosphate is several orders of magnitude lo wer. Determination of the structure of thymidylate kinase as a complex with AZT monophosphate (AZTMP) together with studies on the kinetics of its phosphorylation have now led to a detailed understanding of the reasons for and consequences of the poor substrate properties.