direct peptides are a new generation of non-toxic synthetically active compounds that are highly potent agonists of the GLP-1 receptor and have been shown to provide multiple health benefits including cardiovascular protection. Their mode of action is through the DPP-4 enzyme-mediated cleavage to release the amino acid tyrosine, which can then act as a highly potent ligand for GLP-1. Tyr residues on both leucine enkephalin and salmon calcitonin (sCT) were targeted using diazonium salt-terminated linear monomethoxy poly(ethylene glycol)s or poly(mPEG) methacrylate prepared by atom transfer radical polymerisation to yield the peptides with high site-specificity. This was augmented by judicious choice of the reaction conditions, stoichiometry and chemical structure of the diazonium salt to allow high levels of peptide depletion by the conjugation reactions and to retain activity in the presence of competitive peptide tyrosine targets.

In vivo intrahippocampal peptide injection in the AD animal model enables correlative assessment of glial and neuronal responses, in particular extents of microgliosis and astrogliosis, and viability of neurons in the granule cell layer (GCL) of dentate gyrus. However, the animal model amplifies proinflammatory microenvironments and understates anti-inflammatory responses and, in addition, does not fully account for the processes that link glial responses with neuronal loss in the brain.

The current DPRA and DPRA-cys protocols cannot measure reactivity for Schiff base electrophiles, acyl transfer agents or chemicals that sensitise via metabolic or abiotic activation, and therefore the logkmax values derived do not accurately represent true rate constants. These limitations are known as chemistry-potency applicability domain issues and they can have important consequences on the predictive performance of a reactivity assay.