Dihexa (PNB-0408)

Identity a small synthetic peptide engineered from angiotensin IV (a fragment of the renin-angiotensin system long linked to memory in animals). Its parent, Nle¹-AngIV, showed cognitive effects but poor bioavailability; Dihexa was built to fix that — to be orally active and blood-brain-barrier-penetrant. Developed at Washington State University by Joseph Harding and John Wright. It's small enough (MW ~505) to reach the brain, and is studied as a synaptogenic ("synapse-building") compound. ## Mechanism (as proposed) Dihexa is thought to potentiate HGF/c-Met signaling — the hepatocyte-growth-factor pathway that promotes dendritic-spine formation and synaptogenesis — thereby "building new synapses" rather than merely sharpening existing function (the basis of its mystique). In cultured hippocampal neurons, Dihexa and related AngIV analogs increase spine density, and that effect is abolished when HGF/c-Met is blocked — the main evidence the pathway matters. However, the paper that originally proposed direct high-affinity HGF binding was retracted for fabricated data, so the precise molecular interaction is contested and should be read as a working hypothesis. The pathway is biologically real and independently implicated; the specific mechanistic claims for Dihexa are not securely established.