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...

Descripción completa

Detalles Bibliográficos
Autores principales: Beesu, Mallesh, Caruso, Giuseppe, Salyer, Alex C. D., Khetani, Karishma K., Sil, Diptesh, Weerasinghe, Mihiri, Tanji, Hiromi, Ohto, Umeharu, Shimizu, Toshiyuki, David, Sunil A.
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