Cargando…
Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity
[Image: see text] Human Toll-like receptor 8 (hTLR8) is expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells. Engagement by TLR8 agonists evokes a distinct cytokine profile which favors the development of type 1 helper T cells. Crystal structures of the ectodomain of...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical
Society
2015
|
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601487/ https://www.ncbi.nlm.nih.gov/pubmed/26351878 http://dx.doi.org/10.1021/acs.jmedchem.5b01087 |
_version_ | 1782394559910641664 |
---|---|
author | Beesu, Mallesh Caruso, Giuseppe Salyer, Alex C. D. Khetani, Karishma K. Sil, Diptesh Weerasinghe, Mihiri Tanji, Hiromi Ohto, Umeharu Shimizu, Toshiyuki David, Sunil A. |
author_facet | Beesu, Mallesh Caruso, Giuseppe Salyer, Alex C. D. Khetani, Karishma K. Sil, Diptesh Weerasinghe, Mihiri Tanji, Hiromi Ohto, Umeharu Shimizu, Toshiyuki David, Sunil A. |
author_sort | Beesu, Mallesh |
collection | PubMed |
description | [Image: see text] Human Toll-like receptor 8 (hTLR8) is expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells. Engagement by TLR8 agonists evokes a distinct cytokine profile which favors the development of type 1 helper T cells. Crystal structures of the ectodomain of hTLR8 cocrystallized with two regioisomers of a dual TLR7/8-agonistic N1-substituted imidazoquinolines showed subtle differences in their interactions in the binding site of hTLR8. We hypothesized that the potency of a previously reported best-in-class pure TLR8 agonist, 3-pentylquinoline-2-amine, could be further enhanced by “designing in” functional groups that would mimic key intermolecular interactions that we had observed in the crystal structures. We performed a focused exploration of decorating the quinoline core with alkylamino groups at all possible positions. These studies have led to the identification of a novel TLR8 agonist that was ∼20-fold more potent than the parent compound and displays prominent adjuvantic activity in a rabbit model of immunization. |
format | Online Article Text |
id | pubmed-4601487 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | American
Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-46014872016-09-09 Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity Beesu, Mallesh Caruso, Giuseppe Salyer, Alex C. D. Khetani, Karishma K. Sil, Diptesh Weerasinghe, Mihiri Tanji, Hiromi Ohto, Umeharu Shimizu, Toshiyuki David, Sunil A. J Med Chem [Image: see text] Human Toll-like receptor 8 (hTLR8) is expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells. Engagement by TLR8 agonists evokes a distinct cytokine profile which favors the development of type 1 helper T cells. Crystal structures of the ectodomain of hTLR8 cocrystallized with two regioisomers of a dual TLR7/8-agonistic N1-substituted imidazoquinolines showed subtle differences in their interactions in the binding site of hTLR8. We hypothesized that the potency of a previously reported best-in-class pure TLR8 agonist, 3-pentylquinoline-2-amine, could be further enhanced by “designing in” functional groups that would mimic key intermolecular interactions that we had observed in the crystal structures. We performed a focused exploration of decorating the quinoline core with alkylamino groups at all possible positions. These studies have led to the identification of a novel TLR8 agonist that was ∼20-fold more potent than the parent compound and displays prominent adjuvantic activity in a rabbit model of immunization. American Chemical Society 2015-09-09 2015-10-08 /pmc/articles/PMC4601487/ /pubmed/26351878 http://dx.doi.org/10.1021/acs.jmedchem.5b01087 Text en Copyright © 2015 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Beesu, Mallesh Caruso, Giuseppe Salyer, Alex C. D. Khetani, Karishma K. Sil, Diptesh Weerasinghe, Mihiri Tanji, Hiromi Ohto, Umeharu Shimizu, Toshiyuki David, Sunil A. Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity |
title | Structure-Based
Design of Human TLR8-Specific Agonists with Augmented Potency and
Adjuvanticity |
title_full | Structure-Based
Design of Human TLR8-Specific Agonists with Augmented Potency and
Adjuvanticity |
title_fullStr | Structure-Based
Design of Human TLR8-Specific Agonists with Augmented Potency and
Adjuvanticity |
title_full_unstemmed | Structure-Based
Design of Human TLR8-Specific Agonists with Augmented Potency and
Adjuvanticity |
title_short | Structure-Based
Design of Human TLR8-Specific Agonists with Augmented Potency and
Adjuvanticity |
title_sort | structure-based
design of human tlr8-specific agonists with augmented potency and
adjuvanticity |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601487/ https://www.ncbi.nlm.nih.gov/pubmed/26351878 http://dx.doi.org/10.1021/acs.jmedchem.5b01087 |
work_keys_str_mv | AT beesumallesh structurebaseddesignofhumantlr8specificagonistswithaugmentedpotencyandadjuvanticity AT carusogiuseppe structurebaseddesignofhumantlr8specificagonistswithaugmentedpotencyandadjuvanticity AT salyeralexcd structurebaseddesignofhumantlr8specificagonistswithaugmentedpotencyandadjuvanticity AT khetanikarishmak structurebaseddesignofhumantlr8specificagonistswithaugmentedpotencyandadjuvanticity AT sildiptesh structurebaseddesignofhumantlr8specificagonistswithaugmentedpotencyandadjuvanticity AT weerasinghemihiri structurebaseddesignofhumantlr8specificagonistswithaugmentedpotencyandadjuvanticity AT tanjihiromi structurebaseddesignofhumantlr8specificagonistswithaugmentedpotencyandadjuvanticity AT ohtoumeharu structurebaseddesignofhumantlr8specificagonistswithaugmentedpotencyandadjuvanticity AT shimizutoshiyuki structurebaseddesignofhumantlr8specificagonistswithaugmentedpotencyandadjuvanticity AT davidsunila structurebaseddesignofhumantlr8specificagonistswithaugmentedpotencyandadjuvanticity |