2. Academic Validation
  3. Incorporation of Phosphonate into Benzonaphthyridine Toll-like Receptor 7 Agonists for Adsorption to Aluminum Hydroxide

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.
Alex Cortez 1,  Yongkai Li 1,  Andrew T Miller 1,  Xiaoyue Zhang 1,  Kathy Yue 1,  Jillian Maginnis 1,  Janice Hampton 1,  De Shon Hall 1,  Michael Shapiro 1,  Bishnu Nayak 1,  Ugo D'Oro 2,  Chun Li 1,  David Skibinski 2,  M Lamine Mbow 3,  Manmohan Singh 3,  Derek T O'Hagan 3,  Michael P Cooke 1,  Nicholas M Valiante 3,  Tom Y-H Wu 1
Affiliations

Affiliations

  • 1 Genomics Institute of Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
  • 2 GSK Vaccines , Via Florentina, 1, 53100, Siena, Italy.
  • 3 GSK Vaccines , 45 Sydney Street, Cambridge, Massachusetts 02139, United States.
PMID: 27270029 DOI: 10.1021/acs.jmedchem.6b00489
Abstract

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.

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