Dominant drug targets suppress the emergence of antiviral resistance
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-r...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2014-11-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/03830 |
| _version_ | 1818019223329308672 |
|---|---|
| author | Elizabeth J Tanner Hong-mei Liu M Steven Oberste Mark Pallansch Marc S Collett Karla Kirkegaard |
| author_facet | Elizabeth J Tanner Hong-mei Liu M Steven Oberste Mark Pallansch Marc S Collett Karla Kirkegaard |
| author_sort | Elizabeth J Tanner |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T07:49:27Z |
| format | Article |
| id | doaj.art-0571cfd5f2bc468a80a3125ae20d5046 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:49:27Z |
| publishDate | 2014-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-0571cfd5f2bc468a80a3125ae20d50462022-12-22T02:05:14ZengeLife Sciences Publications LtdeLife2050-084X2014-11-01310.7554/eLife.03830Dominant drug targets suppress the emergence of antiviral resistanceElizabeth J Tanner0https://orcid.org/0000-0001-9445-6620Hong-mei Liu1M Steven Oberste2Mark Pallansch3Marc S Collett4Karla Kirkegaard5Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United StatesDivision of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, United StatesDivision of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, United StatesDivision of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, United StatesViroDefense, Inc., Rockville, United StatesDepartment of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United StatesThe 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.https://elifesciences.org/articles/03830genetic dominancedrug resistancevirus evolutionquasispeciesoligomeric protein |
| spellingShingle | Elizabeth J Tanner Hong-mei Liu M Steven Oberste Mark Pallansch Marc S Collett Karla Kirkegaard Dominant drug targets suppress the emergence of antiviral resistance eLife genetic dominance drug resistance virus evolution quasispecies oligomeric protein |
| title | Dominant drug targets suppress the emergence of antiviral resistance |
| title_full | Dominant drug targets suppress the emergence of antiviral resistance |
| title_fullStr | Dominant drug targets suppress the emergence of antiviral resistance |
| title_full_unstemmed | Dominant drug targets suppress the emergence of antiviral resistance |
| title_short | Dominant drug targets suppress the emergence of antiviral resistance |
| title_sort | dominant drug targets suppress the emergence of antiviral resistance |
| topic | genetic dominance drug resistance virus evolution quasispecies oligomeric protein |
| url | https://elifesciences.org/articles/03830 |
| work_keys_str_mv | AT elizabethjtanner dominantdrugtargetssuppresstheemergenceofantiviralresistance AT hongmeiliu dominantdrugtargetssuppresstheemergenceofantiviralresistance AT mstevenoberste dominantdrugtargetssuppresstheemergenceofantiviralresistance AT markpallansch dominantdrugtargetssuppresstheemergenceofantiviralresistance AT marcscollett dominantdrugtargetssuppresstheemergenceofantiviralresistance AT karlakirkegaard dominantdrugtargetssuppresstheemergenceofantiviralresistance |