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The Imidazoquinoline Toll-Like Receptor-7/8 Agonist Hybrid-2 Potently Induces Cytokine Production by Human Newborn and Adult Leukocytes
Ganapathi, Lakshmi Van Haren, Simon Dowling, David J. Bergelson, Ilana Shukla, Nikunj M. Malladi, Subbalakshmi S. Balakrishna, Rajalakshmi Tanji, Hiromi Ohto, Umeharu Shimizu, Toshiyuki
Ganapathi, Lakshmi
Van Haren, Simon
Dowling, David J.
Bergelson, Ilana
Shukla, Nikunj M.
Malladi, Subbalakshmi S.
Balakrishna, Rajalakshmi
Tanji, Hiromi
Ohto, Umeharu
Shimizu, Toshiyuki
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Abstract
Background:
Newborns and young infants are at higher risk for infections than adults, and manifest suboptimal vaccine responses, motivating a search for novel immunomodulators and/or vaccine adjuvants effective in early life. In contrast to most TLR agonists (TLRA), TLR8 agonists such as imidazoquinolines (IMQs) induce adult-level Th1-polarizing cytokine production from human neonatal cord blood monocytes and are candidate early life adjuvants. We assessed whether TLR8-activating IMQ congeners may differ in potency and efficacy in inducing neonatal cytokine production in vitro, comparing the novel TLR7/8-activating IMQ analogues Hybrid-2, Meta-amine, and Para-amine to the benchmark IMQ resiquimod (R848).
Methods:
TLRA-induced NF-κB activation was measured in TLR-transfected HEK cells. Cytokine production in human newborn cord and adult peripheral blood and in monocyte-derived dendritic cell cultures were measured by ELISA and multiplex assays. X-ray crystallography characterized the interaction of human TLR8 with Hybrid-2.
Results:
Hybrid-2 selectively activated both TLR7 and 8 and was more potent than R848 in inducing adult-like levels of TNF-α, and IL-1β. Consistent with its relatively high in vitro activity, crystallographic studies suggest that absence in Hybrid-2 of an ether oxygen of the C2-ethoxymethyl substituent, which can engage in unfavorable electrostatic and/or dipolar interactions with the carbonyl oxygen of Gly572 in human TLR8, may confer greater efficacy and potency compared to R848.
Conclusions
Hybrid-2 is a selective and potent TLR7/8 agonist that is a candidate adjuvant for early life immunization.
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2015-08-14
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Public Library of Science
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Ganapathi, Lakshmi, Simon Van Haren, David J. Dowling, Ilana Bergelson, Nikunj M. Shukla, Subbalakshmi S. Malladi, Rajalakshmi Balakrishna, Hiromi Tanji, Umeharu Ohto, Toshiyuki Shimizu, Sunil A. David, and Ofer Levy. "The Imidazoquinoline Toll-Like Receptor-7/8 Agonist Hybrid-2 Potently Induces Cytokine Production by Human Newborn and Adult Leukocytes." PLOS ONE PLoS ONE 10.8 (2015): n. pag. http://dx.doi.org/10.1371/journal.pone.0134640.