A polymerase mechanism-based strategy for viral attenuation and vaccine development

Spencer A. Weeks, Cheri A. Lee, Yan Zhao, Eric D. Smidansky, Avery August, Jamie J. Arnold, Craig E. Cameron

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Live, attenuated vaccines have prevented morbidity and mortality associated with myriad viral pathogens. Development of live, attenuated vaccines has traditionally relied on empirical methods, such as growth in nonhuman cells. These approaches require substantial time and expense to identify vaccine candidates and to determine their mechanisms of attenuation. With these constraints, at least a decade is required for approval of a live, attenuated vaccine for use in humans. We recently reported the discovery of an active site lysine residue that contributes to the catalytic efficiency of all nucleic acid polymerases (Castro, C., Smidansky, E. D., Arnold, J. J., Maksimchuk, K. R., Moustafa, I., Uchida, A., Götte, M., Konigsberg, W., and Cameron, C. E. (2009) Nat. Struct. Mol. Biol. 16, 212-218). Here we use a model RNA virus and its polymerase to show that mutation of this residue from lysine to arginine produces an attenuated virus that is genetically stable and elicits a protective immune response. Given the conservation of this residue in all viral polymerases, this study suggests that a universal, mechanism-based strategy may exist for viral attenuation and vaccine development.

Original languageEnglish (US)
Pages (from-to)31618-31622
Number of pages5
JournalJournal of Biological Chemistry
Volume287
Issue number38
DOIs
StatePublished - Sep 14 2012

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Viral Vaccines
Attenuated Vaccines
Vaccines
Viruses
Lysine
RNA Viruses
Pathogens
Nucleic Acids
Arginine
Conservation
Catalytic Domain
RNA
Morbidity
Mutation
Mortality
Growth

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Weeks, S. A., Lee, C. A., Zhao, Y., Smidansky, E. D., August, A., Arnold, J. J., & Cameron, C. E. (2012). A polymerase mechanism-based strategy for viral attenuation and vaccine development. Journal of Biological Chemistry, 287(38), 31618-31622. https://doi.org/10.1074/jbc.C112.401471
Weeks, Spencer A. ; Lee, Cheri A. ; Zhao, Yan ; Smidansky, Eric D. ; August, Avery ; Arnold, Jamie J. ; Cameron, Craig E. / A polymerase mechanism-based strategy for viral attenuation and vaccine development. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 38. pp. 31618-31622.
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Weeks, SA, Lee, CA, Zhao, Y, Smidansky, ED, August, A, Arnold, JJ & Cameron, CE 2012, 'A polymerase mechanism-based strategy for viral attenuation and vaccine development', Journal of Biological Chemistry, vol. 287, no. 38, pp. 31618-31622. https://doi.org/10.1074/jbc.C112.401471

A polymerase mechanism-based strategy for viral attenuation and vaccine development. / Weeks, Spencer A.; Lee, Cheri A.; Zhao, Yan; Smidansky, Eric D.; August, Avery; Arnold, Jamie J.; Cameron, Craig E.

In: Journal of Biological Chemistry, Vol. 287, No. 38, 14.09.2012, p. 31618-31622.

Research output: Contribution to journalArticle

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Weeks SA, Lee CA, Zhao Y, Smidansky ED, August A, Arnold JJ et al. A polymerase mechanism-based strategy for viral attenuation and vaccine development. Journal of Biological Chemistry. 2012 Sep 14;287(38):31618-31622. https://doi.org/10.1074/jbc.C112.401471