Incorporation of Phosphonate into Benzonaphthyridine Toll-like Receptor 7 Agonists for Adsorption to Aluminum Hydroxide

J Med Chem. 2016 Jun 23;59(12):5868-78. doi: 10.1021/acs.jmedchem.6b00489. Epub 2016 Jun 13.


Small molecule Toll-like receptor 7 (TLR7) agonists have been used as vaccine adjuvants by enhancing innate immune activation to afford better adaptive response. Localized TLR7 agonists without systemic exposure can afford good adjuvanticity, suggesting peripheral innate activation (non-antigen-specific) is not required for immune priming. To enhance colocalization of antigen and adjuvant, benzonaphthyridine (BZN) TLR7 agonists are chemically modified with phosphonates to allow adsorption onto aluminum hydroxide (alum), a formulation commonly used in vaccines for antigen stabilization and injection site deposition. The adsorption process is facilitated by enhancing aqueous solubility of BZN analogs to avoid physical mixture of two insoluble particulates. These BZN-phosphonates are highly adsorbed onto alum, which significantly reduced systemic exposure and increased local retention post injection. This report demonstrates a novel approach in vaccine adjuvant design using phosphonate modification to afford adsorption of small molecule immune potentiator (SMIP) onto alum, thereby enhancing co-delivery with antigen.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adsorption
  • Aluminum Hydroxide / chemistry*
  • Animals
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Hydrogen-Ion Concentration
  • Injections, Intramuscular
  • Leukocytes, Mononuclear / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Molecular Structure
  • Naphthyridines / administration & dosage
  • Naphthyridines / chemistry*
  • Naphthyridines / pharmacology*
  • Organophosphonates / administration & dosage
  • Organophosphonates / chemistry*
  • Organophosphonates / pharmacology
  • Spleen / drug effects
  • Structure-Activity Relationship
  • Toll-Like Receptor 7 / agonists*


  • Naphthyridines
  • Organophosphonates
  • Toll-Like Receptor 7
  • Aluminum Hydroxide