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 language | English (US) |
|---|---|
| Pages (from-to) | 31618-31622 |
| Number of pages | 5 |
| Journal | Journal of Biological Chemistry |
| Volume | 287 |
| Issue number | 38 |
| DOIs | |
| State | Published - Sep 14 2012 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Cell Biology
- Molecular Biology
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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 Jon; Cameron, Craig Eugene.
In: Journal of Biological Chemistry, Vol. 287, No. 38, 14.09.2012, p. 31618-31622.Research output: Contribution to journal › Article
TY - JOUR
T1 - A polymerase mechanism-based strategy for viral attenuation and vaccine development
AU - Weeks, Spencer A.
AU - Lee, Cheri A.
AU - Zhao, Yan
AU - Smidansky, Eric D.
AU - August, Avery
AU - Arnold, Jamie Jon
AU - Cameron, Craig Eugene
PY - 2012/9/14
Y1 - 2012/9/14
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.C112.401471
DO - 10.1074/jbc.C112.401471
M3 - Article
VL - 287
SP - 31618
EP - 31622
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 38
ER -