Structural basis for activation of alpha-boranophosphate nucleotide analogues targeting drug-resistant reverse

Related Experiment Video

Updated: Oct 15, 2026

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
10:29

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors

Published on: May 9, 2025

P Meyer1, B Schneider, S Sarfati

  • 1Laboratoire d'Enzymologie et Biochimie Structurales, UPR-9063 CNRS, 91198 Gif-sur-Yvette, France.

The EMBO Journal
|July 19, 2000
PubMed

Insights

New borano-modified nucleoside analogues enhance AIDS chemotherapy by improving drug activation and HIV-1 reverse transcriptase inhibition. These modifications also reduce drug resistance, offering a promising strategy against viral resistance.

Area of Science:

  • Biochemistry
  • Virology
  • Medicinal Chemistry

Background:

  • AIDS chemotherapy faces challenges due to low intracellular concentrations of active nucleoside analogue triphosphates.
  • This leads to incomplete viral replication inhibition and the emergence of drug-resistant HIV-1 strains.

Purpose of the Study:

  • To investigate drug activation by nucleoside diphosphate kinase and inhibition of HIV-1 reverse transcriptase.
  • To explore the potential of alpha-borano modified nucleoside analogues in overcoming limitations in AIDS chemotherapy and drug resistance.

Main Methods:

  • Synthesis of nucleoside analogues with a borano group on the alpha-phosphate.
  • Enzymatic assays to study substrate activity for nucleoside diphosphate kinase and HIV-1 reverse transcriptase.
  • X-ray crystallography to determine the structural basis of enzyme-analogue interactions.
  • Evaluation of drug-resistant reverse transcriptase variants.

Main Results:

  • Borano-modified analogues are substrates for both nucleoside diphosphate kinase and HIV-1 reverse transcriptase.
  • X-ray structures revealed the mechanism of activation and substrate binding.
  • The alpha-borano group enhanced phosphorylation and reverse transcriptase inhibition for AZT and d4T analogues.
  • Reduced pyrophosphorolysis by resistant reverse transcriptases was observed.

Conclusions:

  • Alpha-borano modification improves the efficacy of nucleoside analogues against HIV-1.
  • This modification shows potential in combating drug-resistant viral strains.
  • The strategy may offer a generic approach to enhance antiviral therapies.

More Related Videos

NMR-Based Activity Assays for Determining Compound Inhibition, IC50 Values, Artifactual Activity, and Whole-Cell Activity of Nucleoside Ribohydrolases10:24

NMR-Based Activity Assays for Determining Compound Inhibition, IC50 Values, Artifactual Activity, and Whole-Cell Activity of Nucleoside Ribohydrolases

Published on: June 30, 2019

Nucleoside Triphosphates - From Synthesis to Biochemical Characterization15:22

Nucleoside Triphosphates - From Synthesis to Biochemical Characterization

Published on: April 3, 2014

Related Concept Videos

Antiviral Nucleoside Inhibitors01:22

Antiviral Nucleoside Inhibitors

Antiviral Nucleoside InhibitorsAntiviral nucleoside inhibitors are structural analogs of natural nucleosides that interfere with viral DNA or RNA synthesis. These compounds selectively target viral polymerases due to their resemblance to host nucleosides, thereby disrupting viral genome replication.Mechanism of Acyclovir ActionAcyclovir is a guanosine analog with a three-carbon acyclic side chain. It selectively targets herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2),...
DNA Base Pairing02:27

DNA Base Pairing

Erwin Chargaff’s rules on DNA equivalence paved the way for the discovery of base pairing in DNA. Chargaff’s rules state that in a double-stranded DNA molecule,
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
tRNA Activation02:26

tRNA Activation

Aminoacyl-tRNA synthetases are present in both eukaryotes and bacteria. Though eukaryotes have 20 different aminoacyl-tRNA synthetases to couple to 20 amino acids, many bacteria do not have genes for all of these aminoacyl-tRNA synthetases. Despite this, they still use all 20 amino acids to synthesize their proteins. For instance, some bacteria do not have the gene encoding the enzyme that couples glutamine with its partner tRNA. In these organisms, one enzyme adds glutamic acid to all of the...
Targets for Drug Action: Overview01:26

Targets for Drug Action: Overview

Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
Translesion DNA Polymerases02:10

Translesion DNA Polymerases

Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...