Shukla 2013

Novel Concepts in Vaccine Development

Nikunj Shukla and Sunil David*, Department of Medicinal Chemistry, University of Kansas

Abstract: Vaccines are integral part of everyone’s life. These are prophylactic preparation that improves immunity and helps prevent infections. Vaccines primarily consist of two active components. One component is the antigen, which is the protein, peptide or polysaccharide component of a bacteria or virus against which protection is anticipated. The other important component which helps reduce the dose of antigen and makes vaccines more effective is the adjuvant. Adjuvants help boost the immune system and thereby increase the response to a vaccine. Toll-Like Receptors (TLR) are innate immune receptors which on activation serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. Our extensive work in this field1-4 has led to the identification of a very potent, TLR-7 agonist; 1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (compound 1). This molecule has been utilized to explore various novel concepts towards making effective vaccines. We synthesized a dendrimeric molecule bearing six units of compound 1 and found this dendrimeric molecule 2 to be superior to its monomeric component in terms of quality and quantity of antibody responses.5 Compound 1 was also converted to its isothiocyanate 3 and covalently linked to antigen to construct self-adjuvanting vaccines. Such self-adjuvanting construct was found to be inducing robust, high-affinity immunoglobulin titers in murine models of vaccination.6 Currently we are exploring other chemistries of combining covalently different toll-like receptor agonists to generate novel, dual TLR-2 and TLR-7 active adjuvants.

References

(1) Hood, J. D.; et. al. Human vaccines 2010, 6, 322.

(2) Shukla, N. M.; et. al. Bioorganic & medicinal chemistry letters 2009, 19, 2211.

(3) Shukla, N. M.; et. al. Bioorganic & medicinal chemistry 2011, 19, 3801.

(4) Shukla, N. M.; et. al. Journal of medicinal chemistry 2010, 53, 4450.

(5) Shukla, N. M.; et. al. PloS one 2012, 7, e43612.

(6) Shukla, N. M.; et. al. Bioorganic & medicinal chemistry letters 2011, 21, 3232.