Design, synthesis and immunological evaluation of novel monosaccharide TLR4 agonists

  • Bioorg Chem. 2026 Jun 15:174:109717. doi: 10.1016/j.bioorg.2026.109717.
Zhi-Ming Zhang  1 ,  Yu Wen  1 ,  Meng-Qiang Luo  1 ,  Hai-Long Sun  1 ,  Dong Ding  1 ,  Chun-Miao Liao  1 ,  Jun Guo  2
Affiliations
  • 1. National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensing Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, China.
  • 2. National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensing Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, China. Electronic address: [email protected].
PMID: 41795437 DOI: 10.1016/j.bioorg.2026.109717
Abstract

Monophosphoryl lipid A (MPLA), a Toll-like Receptor 4 (TLR4) agonist, has been utilized as vaccine Adjuvant in several approved human vaccines. However, the complex disaccharide structure of MPLA presents significant challenges for chemical synthesis. To address this limitation, we designed a series of glucosamine-based alkyl 4-phosphate (GAP) compounds. These are monosaccharide lipid A analogues, synthesized by replacing the reducing glucosamine disaccharide of MPLA with an N-diaminoalkyl glycoside unit. Three novel TLR4 agonists, GAP210, GAP212 and GAP214, were successfully synthesized by modulating the length of the secondary acyl chains at the C-2 and C-3 positions of the non-reducing sugar, and were subsequently evaluated as vaccine adjuvants. The results revealed that the length of the secondary acyl chains significantly influenced immune activation. Notably, GAP214-adjuvanted group exhibited 2.5-fold higher IgG level than the positive TLR4 Agonist control after three immunizations. These findings identify the GAP analogues as effective TLR4 agonists and promising candidates for vaccine Adjuvant development.

Keywords
Immunostimulant; Lipid A analogues; MPLA; TLR4 agonist; Vaccine adjuvant.
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