Pathogen-derived peptides in drug targeting and its therapeutic approach

Abstract

Microbial pathogens have developed specific effector proteins that, by interacting with host innate immune factors, present a mechanism to subvert immune responses during infection. Although protein-protein interactions (PPI) formed between effectors and host factors play a crucial role in the pathogenic rewiring of the host signaling, we realized that pathogen-derived and host-interacting motifs provide a vast and unique source of potent modulators of inflammation. We propose a paradigm shift by exploiting microbial effectors not as targets but as valuable tools for the specific manipulation of host signaling pathway – for the advantage of the host. Pathogen-derived peptides, originated from host-pathogen PPIs, could be potential therapeutics for various diseases, including infectious, inflammatory and cancerous disease. Here, we have developed two therapeutic strategies that utilize peptides derived from pathogens, specifically exploiting Toxoplasma gondii GRA9 and Mycobacterium tuberculosis MPT63 and MPT64. In the first series of experiments, we found that the C-terminal of GRA9 (GRA9C) interacts with NLR family pyrin domain containing 3 (NLRP3), regulating the activation of the NLRP3 inflammasome and demonstrating anti-septic effects in mice. In the second series of experiments, multifunctional peptides derived from MPT63 and MPT64 exhibited antimycobacterial properties by targeting infected macrophages, downregulating IFN-β production, and upregulating reactive oxygen species (ROS) production. Collectively, our findings demonstrate how microbial effectors could provide valuable insight into manipulating host inflammatory signaling for therapeutic applications.