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Antivirals that target the host IMPα/β1-virus interface.

Alexander J Martin1, David A Jans1

  • 1Nuclear Signaling Lab., Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia.

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|January 13, 2021
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Summary

Small molecules targeting the importin (IMP) α/β1-virus interface show broad-spectrum antiviral activity. Ivermectin and 4-HPR are promising agents, with clinical trials underway for various viral infections.

Keywords:
SARS-CoV-2Zika virusantiviral agentsdengue virusimportinivermectin

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Area of Science:

  • Virology
  • Molecular Biology
  • Drug Discovery

Background:

  • Nuclear import mediated by importin (IMP) α/β1 is crucial for viral replication.
  • Many viruses, including HIV-1, DENV, and ZIKV, rely on the IMPα/β1-virus interface for infection.
  • Small molecule inhibitors targeting this interface have emerged as a promising antiviral strategy.

Purpose of the Study:

  • To review the antiviral potential of targeting the IMPα/β1-virus interface.
  • To highlight key small molecule inhibitors, ivermectin and 4-HPR.
  • To discuss the clinical progress and therapeutic potential of these agents.

Main Methods:

  • Review of existing literature on IMPα/β1-dependent nuclear import inhibitors.
  • Analysis of high-throughput compound screening data.
  • Summary of clinical trial outcomes and preliminary results for ivermectin and 4-HPR.

Main Results:

  • Ivermectin, an FDA-approved drug, demonstrates broad-spectrum activity against numerous viruses (HIV-1, DENV, ZIKV, SARS-CoV-2).
  • Phase III trials for Dengue and numerous trials for SARS-CoV-2 are ongoing, with preliminary data suggesting clinical benefit.
  • N-(4-hydroxyphenyl) retinamide (4-HPR) specifically targets viral non-structural protein 5 (NS5) and inhibits DENV and ZIKV infections, with Phase II trials planned.

Conclusions:

  • The IMPα/β1-virus interface represents a viable therapeutic target for broad-spectrum antiviral drug development.
  • Ivermectin and 4-HPR show significant promise, supported by ongoing clinical investigations.
  • Rigorous randomized clinical trials are essential to confirm the therapeutic efficacy of these IMPα/β1-targeting agents.