Synthesis of guanidine and quinoline derivatives for the selective inhibition of peptidylarginine deiminase 4 in the context of ACPA-positive rheumatoid arthritis

Rheumatoid arthritis is estimated to affect 1.3 million adults in the United States, with prevalence increasing. Approximately 70% of patients exhibit autoreactivity to citrulline via production of anti-citrullinated protein antibodies (ACPAs) which is linked to the overexpression of citrulline by pathway of peptidylarginine deiminase 4 (PAD4), the enzyme responsible for the posttranslational conversion of arginine to citrulline. High levels of antibodies to citrullinated sites often correlate to more severe clinical disease. In theory, lowering the production of citrulline would limit the available binding sites for ACPAs and reduce immune system-mediated damage to those tissues. PAD4 is calcium-dependent for its activation, making these binding sites attractive targets for inhibition. In addition, these sites may improve selectivity for PAD4 over other PAD isozymes, among which the active site is highly conserved. Given that the calcium binding-sites possess a strong network of acidic residues, phenylguanidine compounds have been investigated due to their robust basicity and site-complementarity. Quinoline compounds also offer a basic nitrogen while mirroring the multi-ring structures of known PAD4 inhibitors while offering a pharmacological precedent for its derivatives lacking in some literature-reported inhibitors. Substituents under study include chlorine and methyl moieties, ideal for maintaining a narrow compound complementary to the calcium site’s shape and for ameliorating the amphipathic character of guanidines for better absorption, while also exploring the formation of multi-guanidine functionalized compounds. Analysis of inhibitory effect will be conducted experimentally via ELISA assay and computationally with AutoDock.