Anti-Infective Peptides to Enhance the Host Innate Response: Design, Development and Delivery

Inducible Nitric Oxide Synthase (iNOS or NOS2) produces Nitric Oxide (NO) and related reactive nitrogen species, which are critical effectors of the host innate response and play key roles in the intracellular killing of bacterial and parasitic pathogens. The SPRY domain- containing SOCS box proteins SPSB1 and SPSB2 are key physiological regulators of this important enzyme. Disrupting the endogenous SPSB-iNOS interaction should prolong the intracellular lifetime of iNOS and enhance the production of NO, and therefore be beneficial in treating chronic and persistent infections such as tuberculosis. By using structure-based design, potent peptide inhibitors of this interaction have been developed.

Inhibitors of the SPSB-iNOS interaction have therapeutic potential as a novel class of anti-infective agents. Various strategies are being pursued to target these peptide inhibitors to macrophages and deliver them to the cytoplasm of these cells. It will then be possible to assess the efficacy of such inhibitors in boosting the capacity of macrophages to destroy infectious pathogens.