iNOS homodimerization as a target for potential new therapeutic agents

Nitric oxide (NO) plays an important role in various physiological processes. Nitric oxide is synthesized by a family of NO synthases (NOS). Of the three isoforms of NOS, inducible NOS (iNOS) is closely linked to inflammatory and autoimmune diseases. The suppression of excess NO production in participating cells may be helpful in improving disease status. This review describes a new mechanism of inhibition of NO production by targeting iNOS dimerization. Nitric oxide synthase isoforms are only active as homodimers. The oxygenase domains of two NOS monomers interact to form the dimer. Certain imidazole derivatives, including PPA250, inhibit this step and suppress NO production. Crystallographic studies have shown that an iNOS dinnerization inhibitor blocks dimer formation by coordinating the heme in the monomer. Oral administration of PPA250 suppressed the development of arthritis after clinical symptoms had appeared in animal models. PPA250 also decreased the serum concentration of NO in mice treated with lipopolysaccharide (LPS). These results indicate that inhibitors of iNOS homodimerization could be useful therapeutic agents for rheumatoid arthritis, septic shock and other diseases in which NO is involved.