Dominant drug targets suppress the emergence of antiviral resistance

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Abstract

The emergence of drug resistance can defeat the successful treatment of pathogens that display high mutation rates, as exemplified by RNA viruses. Here we detail a new paradigm in which a single compound directed against a 'dominant drug target' suppresses the emergence of naturally occurring drug-resistant variants in mice and cultured cells. All new drug-resistant viruses arise during intracellular replication and initially express their phenotypes in the presence of drug-susceptible genomes. For the targets of most anti-viral compounds, the presence of these drug-susceptible viral genomes does not prevent the selection of drug resistance. Here we show that, for an inhibitor of the function of oligomeric capsid proteins of poliovirus, the expression of drug-susceptible genomes causes chimeric oligomers to form, thus rendering the drug-susceptible genomes dominant. The use of dominant drug targets should suppress drug resistance whenever multiple genomes arise in the same cell and express products in a common milieu.

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Elizabeth J Tanner

Stanford University School of Medicine, Stanford, United States

Competing interests
No competing interests declared.
Hong-mei Liu

Centers for Disease Control and Prevention, Atlanta, United States

Competing interests
No competing interests declared.
M Steven Oberste

Centers for Disease Control and Prevention, Atlanta, United States

Competing interests
No competing interests declared.
Mark Pallansch

Centers for Disease Control and Prevention, Atlanta, United States

Competing interests
No competing interests declared.
Marc S Collett

ViroDefense, Inc., Rockville, United States

Competing interests
Marc S Collett, President of ViroDefense, Inc., the sponsoring firm for development of V-073.
Karla Kirkegaard

Stanford University School of Medicine, Stanford, United States

For correspondence
karlak@stanford.edu

Competing interests
No competing interests declared.

Ethics

Animal experimentation: Mice used in these studies were bred and housed under specific pathogen-free conditions at the Stanford University animal care facility, which is accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care, Int. All experiments were approved by Stanford's Institutional Animal Care and Use Committee (Administrative Panel of Laboratory Animal Care). The Assurance number for this panel is A3213-01; the Protocol ID is 9296. For survival studies, mice were euthanized when moribund or upon initial signs of paresis/paralysis.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.