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ABSTRACT Nucleoside-based inhibitors of reverse transcriptase were the first drugs to be used in the chemotherapy of AIDS. After entering the cell, these substances are activated to their

triphosphate form by cellular kinases, after which they are potent chain terminators for the growing viral DNA (ref. 1). The two main factors limiting their efficacy are probably

interrelated. These are the insufficient degree of reduction of viral load at the commencement of treatment and the emergence of resistant variants of the virus. The reason for the

relatively poor suppression of viral replication appears to be inefficient metabolic activation. Thus, for the most extensively used drug, 3′-azido-3′-de-oxythymidine (AZT), whereas

phosphorylation to the monophosphate is facile, the product is a very poor substrate for the next kinase in the cascade, thymidylate kinase2,3. Because of this, although high concentrations

of the monophosphate can be reached in the cell, the achievable concentration of the active triphosphate is several orders of magnitude lower. 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

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our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS DEVIATED BINDING OF ANTI-HBV NUCLEOSIDE ANALOG _E_-CFCP-TP TO THE REVERSE TRANSCRIPTASE ACTIVE SITE ATTENUATES THE

EFFECT OF DRUG-RESISTANT MUTATIONS Article Open access 08 July 2024 DISCOVERY OF DIARYLPYRIMIDINE DERIVATIVES BEARING PIPERAZINE SULFONYL AS POTENT HIV-1 NONNUCLEOSIDE REVERSE TRANSCRIPTASE

INHIBITORS Article Open access 29 April 2023 STRUCTURAL UNDERSTANDING OF NON-NUCLEOSIDE INHIBITION IN AN ELONGATING HERPESVIRUS POLYMERASE Article Open access 24 May 2021 REFERENCES *

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Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Max Planck Institute for Molecular Physiology, Department of Physical Biochemistry, Rheinlanddamm 201, 44139,

Dortmund, Germany Arnon Lavie, Ilme Schlichting, Jochen Reinstein & Roger S. Goody * Max Planck Institute for Molecular Physiology, Department of Structural Biology, Rheinlanddamm 201,

44139, Dortmund, Germany Ingrid R. Vetter * Max Planck Institute for Biophysical Chemistry, Department of Molecular Genetics, 37018, Göttingen, Germany Manfred Konrads Authors * Arnon Lavie

View author publications You can also search for this author inPubMed Google Scholar * Ilme Schlichting View author publications You can also search for this author inPubMed Google Scholar *

Ingrid R. Vetter View author publications You can also search for this author inPubMed Google Scholar * Manfred Konrads View author publications You can also search for this author inPubMed

 Google Scholar * Jochen Reinstein View author publications You can also search for this author inPubMed Google Scholar * Roger S. Goody View author publications You can also search for this

author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Lavie, A., Schlichting, I., Vetter, I. _et al._ The bottleneck in AZT

activation. _Nat Med_ 3, 922–924 (1997). https://doi.org/10.1038/nm0897-922 Download citation * Received: 30 April 1997 * Accepted: 25 June 1997 * Issue Date: 01 August 1997 * DOI:

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