A novel phage-based screening technology for antivirals
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OverviewThis approach is based on the use of phages to develop a new highly sensitive assay platform to reduce time and costs associated with screening of anti-herpetic compounds. The technology could eventually be translated to other viruses. |
Members of the herpesvirus family are important human pathogens. Eight major human herpesviruses that can cause severe diseases in adults and children have been described. The spectrum of diseases associated with these viruses is broad, and the specific risk groups and vulnerable populations often differ depending on the specific virus. However, immunocompromised individuals, including transplant patients, are the most vulnerable regardless of the nature of the herpesvirus. Infection with herpesviruses can also enhance the pathogenicity of the human immunodeficiency virus despite the availability of potent anti-HIV drug regimens. Unfortunately, the use of approved drugs against herpesviruses such as HSV, HCMV and VZV are often associated with severe side effects, the development of drug resistance and a narrow spectrum of antiviral activities. These factors limit the use of available antivirals in the aforementioned clinical settings.
Technical problems in the development of quick, convenient cell-based and/or cell-free assays to screen and assess candidate compounds have hampered the development of anti-herpetic drugs. For most herpesviruses, it is extremely difficult to produce large concentrations of virus stocks in cell culture systems. Moreover, the development of biochemical assays is compromised by the difficulty of expressing and purifying major viral targets.
This ambitious project aims to develop a system of rapid screening for compounds with a spectrum of antiviral activity across all herpesviruses. Dr. Götte and his team will take advantage of the structural and functional similarities among viral DNA polymerases and their orthologs in bacterial phages. Phage-derived chimeric polymerases containing critical parts of the viral enzyme which are sensitive to antiviral drugs will be used to identify novel classes of compounds that inhibit essential functions of the virus. “Given the rapid turnover in phage replication, the bacterial host and the requirements for full-length DNA genome synthesis in a biological environment, we expect the assay to be highly sensitive and unique,” mentions the principal investigator Matthias Götte, Professor at McGill University, adding: “It has the potential to identify new classes of inhibitors that would not be identified with existing technologies.” Plate-based versions of both cell-free and cell-based assays will be developed for the eight described herpesviruses with the ultimate goal to facilitate the discovery of broad-spectrum antivirals. The principle of this technology could then be translated to other viruses and thus address challenges in a broad range of therapeutic indications.
Impact on the drug discovery process
- Reduce the time and expense involved in the discovery of anti-herpetic agents through rapid screening and testing
of small molecules - Improve the treatment of herpes virus infection via the discovery of novel antivirals with a broad-spectrum activity against the whole family of herpesviruses
Key facts
- The vast majority of adults are carriers of herpes viruses
- Herpes virus infection can be life-threatening in people with immune deficiency
- Herpes virus infections are not curable but can be treated
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