Differential Removal of Thymidine Nucleotide Analogues from Blocked DNA Chains by Human Immunodeficiency Virus Reverse Transcriptase in the Presence of Physiological Concentrations of 2′-Deoxynucleoside Triphosphates-Reference-Cited by-同舟云学术

Differential Removal of Thymidine Nucleotide Analogues from Blocked DNA Chains by Human Immunodeficiency Virus Reverse Transcriptase in the Presence of Physiological Concentrations of 2′-Deoxynucleoside Triphosphates

Published:2000-12 Issue:12 Volume:44 Page:3465-3472
ISSN:0066-4804
Container-title:Antimicrobial Agents and Chemotherapy
language:en
Short-container-title:Antimicrob Agents Chemother

Author:

Meyer Peter R.¹,Matsuura Suzanne E.¹,Schinazi Raymond F.²,So Antero G.³,Scott Walter A.¹

Affiliation:

1. Department of Biochemistry and Molecular Biology1 and

2. Department of Pediatrics, Emory University/Veterans Affairs Medical Center, Decatur, Georgia2

3. Department of Medicine,3 University of Miami, Miami, Florida, and

Abstract

ABSTRACT Removal of 2′,3′-didehydro-3′-deoxythymidine-5′-monophosphate (d4TMP) from a blocked DNA chain can occur through transfer of the chain-terminating residue to a nucleotide acceptor by human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). ATP-dependent removal of either d4TMP or 3′-azido-3′-deoxythymidine-5′-monophosphate (AZTMP) is increased in AZT resistant HIV-1 RT (containing D67N/K70R/T215F/K219Q mutations). Removal of d4TMP is strongly inhibited by the next complementary deoxynucleoside triphosphate (50% inhibitory concentration [IC 50 ] of ∼0.5 μM), whereas removal of AZTMP is much less sensitive to this inhibition (IC 50 of >100 μM). This could explain the lack of cross-resistance by AZT-resistant HIV-1 to d4T in phenotypic drug susceptibility assays.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

Link

https://journals.asm.org/doi/pdf/10.1128/AAC.44.12.3465-3472.2000

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