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Rapid Screening of HIV Reverse Transcriptase and Integrase Inhibitors
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Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase.

Kushol Gupta1, Vesa Turkki2, Scott Sherrill-Mix2

  • 1Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Plos Biology
|December 10, 2016
PubMed
Summary
This summary is machine-generated.

Allosteric inhibitors of integrase (ALLINIs) surprisingly block HIV particle assembly, not DNA integration. This occurs by promoting inappropriate polymerization of the integrase protein, offering new targets for drug development.

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Area of Science:

  • Structural Biology
  • Virology
  • Drug Discovery

Background:

  • Allosteric inhibitors of integrase (ALLINIs) target HIV replication by binding to the integrase (IN) protein.
  • ALLINIs unexpectedly inhibit viral particle assembly rather than DNA integration.

Purpose of the Study:

  • To elucidate the inhibitory mechanism of ALLINIs by determining the structure of HIV-1 IN bound to an ALLINI.
  • To understand how ALLINIs disrupt viral replication at the molecular level.

Main Methods:

  • Crystallization of full-length HIV-1 IN in complex with the ALLINI GSK1264.
  • Determination of the complex structure at 4.4 Å resolution using X-ray crystallography.
  • Analysis of inhibitor-induced IN multimerization through engineered amino acid substitutions and HIV escape mutants.

Main Results:

  • The structure revealed GSK1264 binding between the C-terminal domain (CTD) and catalytic core domain of IN.
  • IN formed an open polymer mediated by inhibitor-bridged contacts between dimers.
  • Mutations at the inhibitor interface blocked ALLINI-induced multimerization and reduced ALLINI sensitivity in escape mutants.

Conclusions:

  • ALLINIs inhibit HIV particle assembly by inducing inappropriate IN polymerization via CTD-catalytic core domain interactions.
  • The identified inhibitor-binding interface provides a basis for optimizing ALLINI-based therapeutics.
  • Understanding this mechanism opens new avenues for developing novel anti-HIV drugs.