Amyloid plaques in brain, composed of aggregates of amyloid-␤ peptide, play a central role in the pathogenesis of Alzheimer's disease and represent a good target for treatment. We have shown previously that a 5-amino acid ␤-sheet breaker peptide (iA␤5p), end-protected, has the ability to induce a dramatic reduction in amyloid deposition in two different transgenic Alzheimer's models (Permanne, B., Adessi, C., Saborio, G. P., Fraga, S., Frossard, M.-J., Dewachter, I., Van Dorpe, J., Banks, W. A., Van Leuven, F., and Soto, C. (2002) FASEB J. 16, 860 -862). The aim of this study was to evaluate the effect of chemical modifications of the peptide bonds at the metabolite cleavage sites on the pharmacological properties of iA␤5p derivatives. Using a rational approach, peptide analogs were designed and tested for in vitro activity and enzymatic stability. One peptide analog containing a methyl group introduced at the nitrogen atom of one amide bond showed increased stability in vitro, a 10-fold higher in vivo half-life, and good brain uptake compared with iA␤5p while maintaining a similar activity in vitro. Our results suggest that the pharmacological profile of ␤-sheet breaker peptides can be improved to produce compounds with drug-like properties that might offer a new promise in the treatment of Alzheimer's disease.Alzheimer's disease is a degenerative disorder of the brain for which there is no cure or effective treatment. Recent studies suggest that cerebral amyloid plaques play a central role in the pathogenesis of the disease (1-3). An attractive therapeutic strategy for Alzheimer's disease is to block the early steps of misfolding and aggregation of the soluble amyloid-␤ peptide (A␤) 1 (3). We proposed that short synthetic peptides capable of binding A␤ but unable to become part of a ␤-sheet structure (␤-sheet breaker peptides) may destabilize the amyloidogenic A␤ conformer and hence preclude amyloid formation (3-5). A major drawback with the use of peptides as drugs in neurological diseases is their rapid metabolism by proteolytic enzymes and their poor blood-brain barrier (BBB) permeability (6 -9). We reported previously that a 5-residue synthetic peptide (iA␤5, LPFFD) was able to inhibit and disassemble amyloid fibrils in vitro, to prevent A␤ neurotoxicity in cell culture, to arrest deposition of amyloid lesions, and to induce dissolution of preformed plaques in a rat brain model of amyloidosis (4,5,10). More recently, we showed that iA␤5 with N-and C-terminal protections to minimize exopeptidase cleavage (iA␤5p, Ac-LPFFD-NH 2 ) was rapidly taken up by the brain and reduced in vivo amyloid deposition and cerebral damage in a double transgenic animal model of Alzheimer's disease (11). In addition, this compound showed low toxicity, low immunogenicity, and high solubility. The weakest aspect of this compound is its relatively short in vivo half-life.The goal of this work was to introduce a series of chemical modifications into iA␤5p aiming to increase stability and simultaneously maintaining (or enhancing) pot...

These data demonstrate a differential modulation of S1PRs in MS lesions, which may have an impact on S1PR-directed therapies.

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