The Cunningham lab has discovered that the CHEC peptides are novel potential anti-inflammation therapeutics as inhibitors of secreted phospholipase A2 (sPLA2).  Elevated levels of sPLA2 enzymes and the resulting biochemical signaling cascade have been implicated in the pathology of several neurological diseases, including multiple sclerosis, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, and systemic inflammation.  sPLA2 enzymes are attractive therapeutic targets because of their accessibility in circulation, as well as the connection to both inflammatory and cell death mechanisms.  There is a lack of effective treatments for most neurological disorders, so exploring different modes of neuronal protection may be advantageous in drug design.

In this work, modifications of the cell survival and anti-inflammatory peptide CHEC-9 have been synthesized and tested in vivo.  One modification, termed CHEC-7, is shorter in amino acid length, and with the removal of two hydrophobic amino acids, may have greater cell uptake and higher therapeutic efficacy.  A single subcutaneous injection CHEC-7 in a rat model inhibited the acute rise of plasma sPLA2 activity and provided a more prolonged inhibition of activity than that of CHEC-9.  As an uncompetitive inhibitor, CHEC peptides are optimal for enzyme inhibition therapy because they are more effective with substrate accumulation.  Neuroinflammatory disorders are characterized by cascading increases in sPLA2 and its substrates, both systemically and in the central nervous system.