Bacterial signal peptidase inhibitors and uses thereof
OwnerStephen Ashman, Michael T. Black +3inventors
InventorsStephen Ashman, Michael T. Black, Gordon Bruton, Alfred John Humphries, Keith James Millan Moore
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Abstract
Substrates for bacterial signal peptidases and their use in assays to detect inhibitors of these enzymes.
Claims13
A compound of formula (I):
- [A][A1][A2][A3]*[A4] (I)
- where:
- * is the cleavage site
- [A] is selected from:
- (i) 2 to 12 hydrophobic amino acid residues substituted at the N-terminus by C1-5 alkanoyl or phenylC1-4alkanoyl optionally substituted by C1-4alkyl, C1-4alkoxy or halogen;
- and
- (ii) a hydrophobic acyl residue;
- [A1] is 1 to 3 amino acid residues selected from A, F, G, I, L, M, N, S, T, V;
- [A2] is 3 amino acid residues selected from those favoured in a beta- or helical turn;
- [A3] is 3 amino acid residues X—B-Z, where X is selected from A, G, S, T, and V, B is any amino acid residue and Z is selected from A, G and S;
- and
- [A4] is 2 to 8 amino acid residues chosen predominantly from those that are favoured in beta-turns and enhance water solubility:
- and optionally wherein:
- one amino acid in one of [A1] and [A2] is replaced by X1 comprising an amino acid bearing a marker group;
- and one amino acid in [A4] other than the residue immediately adjacent to [A3] is replaced by X2 comprising an amino acid bearing a marker group;
- such that X1 and X2 form a marker pair;
- [A2] residues are selected from G, L, N, P, S and T;
- X is selected from A, S and V;
- B is selected from D, F, H, I, K, L, N, Q, R, V or Y;
- and
- Z is selected from A and S.
A compound according to any preceding claim wherein [A2] is 3 amino acid residues selected from A, F, G, I, L, N, P, S, T, V.
A compound according to any preceding claim wherein X is A, S or V, B is a neutral or basic amino acid residue and Z is A or S.
A compound according to any preceding claim wherein the first amino acid residue in [A4] is A, D, E, Q or S and the remaining amino acid residues are selected from A, D, E, F, G, I, K, L, N, P, Q, R, S, T and V with not more than two of each of G, P and R and no more than 2 amino acid residues being selected from F, I, L and V.
A compound according to any preceding claim wherein the X1/X2 marker group pair is a fluorophore pair or a fluorophore/biotin ligand combination.
13 An assay system for testing for bacterial signal peptidase inhibitors which comprises contacting a bacterial signal peptidase and a compound of formula (I) according to claim 1 with a test compound and measuring inhibition of the cleavage of the compound of formula (I) by the peptidase.
Dependencies are inferred from the claim text.