The influenza virus is responsible for hundreds of thousands of deaths and millions of hospitalizations annually. While annual vaccines are available, their efficacy is limited towards immunocompromised individuals and relies on the correct prediction of viral mutations. Accordingly, there is a need for novel therapeutics which can combat this disease. Among the most important biochemical targets, much attention has been devoted towards the RNA-dependent RNA polymerase PA N-terminal (PAN) endonuclease, which is a critical component of the viral replication machinery. Metal-binding pharmacophores (MBPs) are critical for binding the catalytic metal centers of metalloenzymes such as PAN; however, despite recent developments, many MBPs still rely on a carboxylic acid moieties, which may be susceptible to pharmacological liabilities. To overcome this limitation, several metal-binding isosteres (MBIs) were designed and synthesized where the carboxylic acid moiety is replaced with isosteric metal binding groups that can modulate pharmacokinetic properties. The binding of novel MBIs were examined using X-ray crystallography, revealing novel[CS1] interactions between the inhibitor and the active site metal. This study details the rational design, synthesis and evaluation of MBIs capable of potent PAN inhibition.

Metal-binding pharmacophore isosteres as inhibitors of influenza endonuclease

ACS Spring 2022

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