Beta-secretase substrates and uses thereof
AssigneeMerck & Co., Inc.
InventorsStephen F. Brady, James E. Bruce, Elizabeth Chen-Dodson, Victor Garsky, Yueming Li, Mohinder Sardana, Jules A. Shafer, Xiaoting Tang
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Abstract
The present invention provides synthetic β-secretase peptide substrates useful in various assays for measuring β-secretase activity. Antibodies that recognize the synthetic substrates and uses of the antibodies in various assays are disclosed. The herein disclosed peptide substrates are hydrolyzed at rates substantially faster than the attendant Swedish mutant APP from which the substrate sequences are derived.
Claims11
A method for assaying for decreased β-secretase activity comprising measuring a cleavage product produced from cleavage by β-secretase of β-amyloid precursor protein (APP) substrate comprising a β-secretase peptide substrate, comprising a β-secretase cleavage site and having the formula P4-P3-P2-P1-P1′-P2′-P3′-P4′, where
- P4 is selected from the group consisting of D, E, I, L and V;
- P3 is selected from the group consisting of L, I, V and N;
- P2 is selected from the group consisting of F, Y, E and N;
- P1 is selected from the group consisting of F, I, L and Y;
- P1′ is selected from the group consisting of A, E, S, I, L and D;
- P2′ is selected from the group consisting of V, I, L and A;
- P3′ is selected from the group consisting of V, I, L, E and Y;
- and
- P4′ is selected from the group consisting of P, W and F;
- where P4-P3-P2-P1-P1′-P2′-P3′-P4′ cannot simultaneously be chosen such that they comprise the Swedish mutation β-secretase cleavage site (SEQ ID NO:
- 257);
- and
- where a decrease in β-secretase activity is determined when the amount of the cleavage product is decreased relative to the amount of the cleavage product produced from an APP substrate having the Swedish mutation β-secretase cleavage site (SEQ ID No:
- 257).
Dependencies are inferred from the claim text.