2. Academic Validation
  3. Structure-Activity Relationships toward the Identification of a High-Potency Selective Human Toll-like Receptor-7 Agonist

Structure-Activity Relationships toward the Identification of a High-Potency Selective Human Toll-like Receptor-7 Agonist

  • J Med Chem. 2024 May 23;67(10):8346-8360. doi: 10.1021/acs.jmedchem.4c00464.
Deepender Kaushik 1,  Arshpreet Kaur 1,  Madhuri T Patil 2,  Binita Sihag 1,  Sakshi Piplani 3 4,  Isaac Sakala 3 4,  Yoshikazu Honda-Okubo 3 4,  Saravanan Ramakrishnan 5,  Nikolai Petrovsky 3 4,  Deepak B Salunke 1 6
Affiliations

Affiliations

  • 1 Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh 160014, India.
  • 2 Mehr Chand Mahajan DAV College for Women, Sector 36A, Chandigarh 160 036, India.
  • 3 Vaxine Pty Ltd., 11 Walkley Avenue, Warradale, South Australia 5046, Australia.
  • 4 College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia.
  • 5 Immunology Section, Indian Veterinary Research Institute, Bareilly 243122, India.
  • 6 National Interdisciplinary Centre of Vaccines, Immunotherapeutics and Antimicrobials (NICOVIA), Panjab University, Chandigarh 160 014, India.
PMID: 38741265 DOI: 10.1021/acs.jmedchem.4c00464
Abstract

Toll-like Receptor (TLR)-7 agonists are immunostimulatory vaccine adjuvants. A systematic structure-activity relationship (SAR) study of TLR7-active 1-benzyl-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine led to the identification of a potent hTLR7-specific p-hydroxymethyl IMDQ 23 with an EC50 value of 0.22 μM. The SAR investigation also resulted in the identification of TLR7 selective carboxamide 12 with EC50 values of 0.32 μM for hTLR7 and 18.25 μM for hTLR8. In the vaccination study, TLR7-specific compound 23 alone or combined with alum (aluminum hydroxide wet gel) showed Adjuvant activity for a spike protein immunogen in mice, with enhanced anti-spike antibody production. Interestingly, the Adjuvant system comprising carboxamide 12 and alum showed prominent Adjuvant activity with high levels of IgG1, IgG2B, and IgG2C in immunized mice, confirming a balanced Th1/Th2 response. In the absence of any apparent toxicity, the TLR7 selective agonists in combination with alum may make a suitable vaccine Adjuvant.

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