A Synthetic Multivalent Lipopeptide Derived from Pam3CSK4 with Irreversible Influenza Inhibition and Immuno-Stimulating Effects

The activation of the host adaptive immune system is crucial for eliminating viruses. However, influenza infection often suppresses the innate immune response that precedes adaptive immunity, and the adaptive immune responses are typically delayed. Dendritic cells, serving as professional antigen-presenting cells, have a vital role in initiating the adaptive immune response. In this study, an immuno-stimulating antiviral system (ISAS) is introduced, which is composed of the immuno-stimulating adjuvant lipopeptide Pam3CSK4 that acts as a scaffold onto which it is covalently bound 3 to 4 influenza-inhibiting peptides. The multivalent display of peptides on the scaffold leads to a potent inhibition against H1N1 (EC50 = 20 nM). Importantly, the resulting lipopeptide, Pam3FDA, shows an irreversible inhibition mechanism. The chemical modification of peptides on the scaffold maintains Pam3CSK4's ability to stimulate dendritic cell maturation, thereby rendering Pam3FDA a unique antiviral. This is attributed to its immune activation capability, which also acts in synergy to expedite viral elimination. Pam3FDA, a representative molecule of an immuno-stimulating antiviral system (ISAS) combining the TLR1/2 agonist Pam3CSK4 with multivalent influenza-binding peptides, shows no cytotoxicity up to 500 mu M and potent H1N1 inhibition (EC50 = 20 nM) with an irreversible mechanism. It also retains dendritic cell maturation stimulation, crucial for inducing an adaptive immune response to influenza infection. image