Diamino Allose Phosphates: Novel, Potent, and Highly Stable Toll-like Receptor 4 Agonists

Most known synthetic toll-like receptor 4 (TLR4) agonists are carbohydrate-based lipid-A mimetics containing several fatty acyl chains, including a labile 3-O-acyl chain linked to the C-3 position of the non-reducing sugar known to undergo cleavage impacting stability and resulting in loss of activi...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2023-10, Vol.66 (20), p.13900-13917
Main Authors: Khalaf, Juhienah K., Bess, Laura S., Walsh, Lois M., Ward, Janine M., Johnson, Craig L., Livesay, Mark T., Jackson, Konner J., Evans, Jay T., Ryter, Kendal T., Bazin-Lee, Hélène G.
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Most known synthetic toll-like receptor 4 (TLR4) agonists are carbohydrate-based lipid-A mimetics containing several fatty acyl chains, including a labile 3-O-acyl chain linked to the C-3 position of the non-reducing sugar known to undergo cleavage impacting stability and resulting in loss of activity. To overcome this inherent instability, we rationally designed a new class of chemically more stable synthetic TLR4 ligands that elicit robust innate and adaptive immune responses. This new class utilized a diamino allose phosphate (DAP) scaffold containing a nonhydrolyzable 3-amide bond instead of the classical 3-ester. Accordingly, the DAPs have significantly improved thermostability in aqueous formulations and potency relative to other known natural and synthetic TLR4 ligands. Furthermore, the DAP analogues function as potent vaccine adjuvants to enhance influenza-specific antibodies in mice and provide protection against lethal influenza virus challenges. This novel set of TLR4 ligands show promise as next-generation vaccine adjuvants and stand-alone immunomodulators.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c00724