Linker chemistry and connectivity fine-tune the immune response and kinetic solubility of conjugated NOD2/TLR7 agonists

Janež, Špela (author), Guzelj, Samo (author), Jakopin, Žiga (author)

There is a growing interest in developing novel immune potentiators capable of eliciting a cellular immune response. We tackle this challenge by harnessing the synergistic cross-activation between two innate immune receptors─the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and Toll-like receptor 7 (TLR7). Herein, we investigate the structure–activity relationship of a series of novel conjugated NOD2/TLR7 agonists incorporating a variety of flexible aliphatic, poly(ethylene glycol)-based and triazole-featuring linkers. Our findings reveal potent immune-enhancing properties of conjugates in human primary peripheral blood mononuclear cells, characterized by a Th1/Th17 polarized cytokine response. Importantly, we demonstrate that both the chemistry of the linker and the site of linkage affect the immune fingerprint and the kinetic solubility of these conjugated agonists. These results shed further light on the immunostimulatory potential of NOD2/TLR7 cross-activation and provide insights for designing innovative immune potentiators.

• Language: English
• Keywords: agonists, amines, conjugate acid-base pairs, peptides, proteins, solubility
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 1723–1731
• Numbering: Vol. 35, iss. 11
• PID: 20.500.12556/RUL-165195
• UDC: 615.4:54:616.097
• ISSN on article: 1520-4812
• DOI: 10.1021/acs.bioconjchem.4c00321
• COBISS.SI-ID: 211169539
• Publication date in RUL: 26.11.2024

Record is a part of a journal

• Title: Bioconjugate chemistry
• Shortened title: Bioconjug. chem.
• Publisher: American Chemical Society
• ISSN: 1520-4812
• COBISS.SI-ID: 3419674

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: agonisti, amini, konjugirani kislinsko-bazični pari, peptidi, proteini, topnost, imunski odziv, farmacevtska kemija