PHAR 562 Lecture Notes - Lecture 23: Amyloid Precursor Protein Secretase, Semagacestat, Psen1
12 Feb 2020
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Document Summary
Product: a -ctf, which is converted to a peptides via -secretase. Bace leaves a residue of app in the membrane. It"s a membrane-bound step, which causes issues when trying to inhibit gamma-secretase as you inhibit the proteasome activity used to degrade the other proteins. Approach: prevent the first step of the series of reactions leading to a release. Verubacestat has a very good affinity to human bace: favourable pharmacological characteristics. Thought to be because -amyloid keeps on aggregating in already-formed deposits. You need to understand the mechanisms of an enzyme to inhibit the right enzymatic activity: i. e. you want to prevent app cleavage and enhance a 42 site 34/35 cleavage. Inhibiting isn"t a good idea because these complexes isn"t -amyloid-specific. Companies are looking at modulators for these complexes. Mutations in the complex containing presenilin 1 and 2 causes fad, and you can predict age of onset based on location of mutation.
