Multicomponent Macrocyclic IL-17a Modifier

[Image: see text] IL-17a is a major inflammation target, with several approved antibodies in clinical use. Small-molecule IL-17a antagonists are an emerging hot topic, with the recent advancement of three compounds into clinical trials. Here, we describe the design, discovery, synthesis, and screeni...

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Autores principales: Abdelraheem, Eman, Lubberink, Max, Wang, Wenja, Li, Jingyao, Reyes Romero, Atilio, van der Straat, Robin, Du, Xiaochen, Groves, Matthew, Dömling, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9465830/
https://www.ncbi.nlm.nih.gov/pubmed/36105327
http://dx.doi.org/10.1021/acsmedchemlett.2c00257
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author Abdelraheem, Eman
Lubberink, Max
Wang, Wenja
Li, Jingyao
Reyes Romero, Atilio
van der Straat, Robin
Du, Xiaochen
Groves, Matthew
Dömling, Alexander
author_facet Abdelraheem, Eman
Lubberink, Max
Wang, Wenja
Li, Jingyao
Reyes Romero, Atilio
van der Straat, Robin
Du, Xiaochen
Groves, Matthew
Dömling, Alexander
author_sort Abdelraheem, Eman
collection PubMed
description [Image: see text] IL-17a is a major inflammation target, with several approved antibodies in clinical use. Small-molecule IL-17a antagonists are an emerging hot topic, with the recent advancement of three compounds into clinical trials. Here, we describe the design, discovery, synthesis, and screening of macrocyclic compounds that bind to IL-17a. We found that all currently described IL-17a modifiers belong to the same pharmacophore model, likely resulting in a similar receptor binding mode on IL-17a. A pipeline of pharmacophore analysis, virtual screening, resynthesis, and protein biophysics resulted in a potent IL-17a macrocyclic modifier.
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spelling pubmed-94658302022-09-13 Multicomponent Macrocyclic IL-17a Modifier Abdelraheem, Eman Lubberink, Max Wang, Wenja Li, Jingyao Reyes Romero, Atilio van der Straat, Robin Du, Xiaochen Groves, Matthew Dömling, Alexander ACS Med Chem Lett [Image: see text] IL-17a is a major inflammation target, with several approved antibodies in clinical use. Small-molecule IL-17a antagonists are an emerging hot topic, with the recent advancement of three compounds into clinical trials. Here, we describe the design, discovery, synthesis, and screening of macrocyclic compounds that bind to IL-17a. We found that all currently described IL-17a modifiers belong to the same pharmacophore model, likely resulting in a similar receptor binding mode on IL-17a. A pipeline of pharmacophore analysis, virtual screening, resynthesis, and protein biophysics resulted in a potent IL-17a macrocyclic modifier. American Chemical Society 2022-08-12 /pmc/articles/PMC9465830/ /pubmed/36105327 http://dx.doi.org/10.1021/acsmedchemlett.2c00257 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Abdelraheem, Eman
Lubberink, Max
Wang, Wenja
Li, Jingyao
Reyes Romero, Atilio
van der Straat, Robin
Du, Xiaochen
Groves, Matthew
Dömling, Alexander
Multicomponent Macrocyclic IL-17a Modifier
title Multicomponent Macrocyclic IL-17a Modifier
title_full Multicomponent Macrocyclic IL-17a Modifier
title_fullStr Multicomponent Macrocyclic IL-17a Modifier
title_full_unstemmed Multicomponent Macrocyclic IL-17a Modifier
title_short Multicomponent Macrocyclic IL-17a Modifier
title_sort multicomponent macrocyclic il-17a modifier
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9465830/
https://www.ncbi.nlm.nih.gov/pubmed/36105327
http://dx.doi.org/10.1021/acsmedchemlett.2c00257
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