%0 Journal Article
%T Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry
%A Andrew K. Sewell
%A Ann Ager
%A Anya Lissina
%A Awen Gallimore
%A Bruno Laugel
%A David A. Price
%A David K. Cole
%A Emily S.J. Edwards
%A Garry Dolton
%A Han Siean Lee
%A Jamie Rossjohn
%A Johanne M. Pentier
%A John J. Miles
%A Julia Makinde
%A Katherine K. Matthews
%A Katie Tungatt
%A Kristin Ladell
%A Mai Ping Tan
%A Mathew Clement
%A Meriem Attaf
%A Pierre J. Rizkallah
%A Richard J. Clark
%A Sarah A.E. Galloway
%A Scott R. Burrows
%A Stephanie Gras
%A Thomas S. Watkins
%A Yide Wong
%J The Journal of Clinical Investigation
%D 2018
%R 10.1172/JCI91512
%X Polypeptide vaccines effectively activate human T cells but suffer from poor biological stability, which confines both transport logistics and in vivo therapeutic activity. Synthetic biology has the potential to address these limitations through the generation of highly stable antigenic ˇ°mimicsˇ± using subunits that do not exist in the natural world. We developed a platform based on D¨Camino acid combinatorial chemistry and used this platform to reverse engineer a fully artificial CD8+ T cell agonist that mirrored the immunogenicity profile of a native epitope blueprint from influenza virus. This nonnatural peptide was highly stable in human serum and gastric acid, reflecting an intrinsic resistance to physical and enzymatic degradation. In vitro, the synthetic agonist stimulated and expanded an archetypal repertoire of polyfunctional human influenza virus¨Cspecific CD8+ T cells. In vivo, specific responses were elicited in naive humanized mice by subcutaneous vaccination, conferring protection from subsequent lethal influenza challenge. Moreover, the synthetic agonist was immunogenic after oral administration. This proof-of-concept study highlights the power of synthetic biology to expand the horizons of vaccine design and therapeutic delivery
%U https://www.jci.org/articles/view/91512