Structural studies and cyclization of the neuroprotective octapeptide NAPVSIPQ to improve cell permeability

A secondary structural model for the neuroprotective octapeptide NAPVSIPQ in DMSO was developed using a combination of NMR spectroscopy and molecular dynamics simulations. On the basis of this model, four cyclized analogues of NAPVSIPQ were designed to improve its cell permeability with a long-term view to oral delivery and increasing central nervous system (CNS) penetration. Testing of cell permeability through a monolayer of Caco-2 cells demonstrated that three of the four cyclized analogues did exhibit up to 5-fold improved permeability through the Caco-2 monolayer. Additionally, none of the peptides appears to be P-glycoprotein substrates subject to cellular efflux.