PHOSPHINO PEPTIDES AS INHIBITORS OF HUMAN β- SECRETASE (BACE1)

摘要

The octapeptide OM00-3 containing a hydroxyethylene (HE) isostere is an inhibitor of BACE1 based on the sequence of Swedish mutant β-amyloid precursor protein (APP). Since BACE1, a unique member of the pepsin family of aspartyl proteases, initiates the pathogenic processing of APP by cleaving at the N-terminus, it is a molecular target for therapeutic intervention in Alzheimer's disease (AD). The phosphinic acid moiety is an excellent mimic of the tetrahedral transition state of amide bond hydrolysis. Therefore we used the sequence of inhibitor OMOO-3 and replaced the HE isostere by a phosphino dipeptide (PDP) isostere to generate a phosphino peptide (PP) (FMOM00-3P) as inhibitor of BACE1 (Fig. 1).