Small molecule inhibitors of influenza virus nucleoprotein

点击翻译按钮获取中文摘要

Influenza is a continuing worldwide public health threat, with seasonal activity that is not adequately controlled by the yearly vaccine program. The severity of this problem is likely to increase with emergence of new influenza virus strains in the human population, and this situation is made even more complex by the COVID-19 pandemic. Both COVID-19 and the 2009 H1N1 influenza pandemics are reminders of the challenge posed by emergent viruses, and they also highlight weaknesses in global preparedness should additional threats arise. Despite existing seasonal vaccines and two classes of chemical pharmaceuticals in current use, there is an urgent need for new anti-influenza therapeutic agents to provide broader coverage, ensure against emergence of drug resistance and prepare for future inevitable pandemics. This Phase I STTR application is to develop potent inhibitors to a novel viral target, the nucleoprotein NP. We have identified and characterized two inhibitor classes, with promising affinity and potency, lack of cytotoxicity and good PK properties. The goals of Phase I are to demonstrate in vivo efficacy in the mouse model, select and characterize escape mutants in cell culture, and further explore one of our series with excellent opportunities for additional medicinal chemistry. Included in this effort is the important goal of creating broad-spectrum antivirals that are active against H1N1 and H3N2 seasonal strains – which is achievable given the highly conserved nature of the NP target. Our approach is divided among three, integrated Specific Aims. In Aim 1 the BALB/c mouse infection model will be used for efficacy studies of leads JJNP9-4 and MC-2, based on successful MTD and PK studies in the mouse. Several parameters will be measured as indicators of efficacy, including mortality, body weight, viral load in the lung and other standard behavioral and physical parameters. In Aim 2, JJNP9-4 and MC-2 will be used for selection of virus escape mutants, followed by sequencing of the mutants, reverse genetic construction of drug-resistant variants, and characterization of viral fitness of the escape mutants. The results will inform future structural studies to identify the binding sites of the inhibitors. In Aim 3 the potency of one inhibitor series will be addressed by developing an SAR with the synthesis of individual analogs and combinatorial libraries Two top-prioritized analogs will be used for MTD, PK and efficacy studies in the mouse model of infection.