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. 2024 Dec 19;16(1):80-88.
doi: 10.1021/acsmedchemlett.4c00463. eCollection 2025 Jan 9.

Structure-Based Design of Novel TLR7/8 Agonist Payloads Enabling an Immunomodulatory Conjugate Approach

Yam B Poudel  1 , Julian C Lo  1 , Derek J Norris  2 , Matthew Cox  1 , Liqi He  1 , Walter L Johnson  1 , Murugaiah A M Subbaiah  3 , Santigopal Mondal  3 , Soodamani Thangavel  3 , Lakshumanan Subramani  3 , Maheswara Reddy  3 , Suraksha Jain  3 , Dahlia R Weiss  1 , Prasanna Sivaprakasam  2 , David Critton  2 , Dawn Mulligan  2 , Chunshan Xie  2 , Payal Dhar  1 , Yvonne Li  1 , Emanuela Sega  1 , Sayumi Yamazoe  1 , Ashvinikumar V Gavai  2 , Arvind Mathur  2 , Christoph W Zapf  4 , Eugene P Chekler  1
Affiliations

Structure-Based Design of Novel TLR7/8 Agonist Payloads Enabling an Immunomodulatory Conjugate Approach

Yam B Poudel et al. ACS Med Chem Lett. .

Abstract

Dual activation of the TLR7 and TLR8 pathways leads to the production of type I interferon and proinflammatory cytokines, resulting in efficient antigen presentation by dendritic cells to promote T-cell priming and antitumor immunity. We developed a novel series of TLR7/8 dual agonists with varying ratios of TLR7 and TLR8 activity for use as payloads for an antibody-drug conjugate approach. The agonist-induced production of several cytokines in human whole blood confirmed their functional activity. Structure-activity relationship studies guided by structure-based drug design are described.

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Conflict of interest statement

The authors declare no competing financial interest.

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