Stapled antimicrobial peptides (stamps) and uses thereof
AssigneeLytica Therapeutics, Inc.
InventorsRida Mourtada, Warren A. Dorsch
Life of this patent
Estimating the term…
Abstract
Provided are stapled antimicrobial peptides (i.e., StAMPs) and methods of using the same (e.g., for treating bacterial infections caused by Gram-negative bacteria). In certain embodiments, the stapled peptides are based on the amino acid sequence of the antimicrobial peptide Magainin II, but include certain modifications that have been found to confer advantageous properties (e.g., improved antimicrobial activity, selectivity for killing Gram-negative bacteria, and/or reduced toxicity). Also provided are unstapled peptides which can serve as synthetic precursors to the stapled peptides provided herein
Claims119
A peptide comprising the amino acid sequence:
- (SEQ ID NO:
- 1)
- G X1 G K F X2 H S K K K F G K A X3 V G E X4,
- or a pharmaceutically acceptable salt thereof, wherein:
- X1, X2, X3, and X4 are independently amino acids;
- X1 and X2 are connected via a crosslink, and X3 and X4 are connected via a crosslink;
- and
- the amino acid sequence includes 1 to 9 amino acid substitutions, inclusive, at positions other than X1, X2, X3, and X4;
- provided that at least one amino acid substitution is at H7, S8, G18, or E19;
- and provided that the amino acid substitution at G18 is not G18H.
A peptide comprising the amino acid sequence:
- (SEQ ID NO:
- 1)
- G X1 G K F X2 H S K K K F G K A X3 V G E X4,
- or a pharmaceutically acceptable salt thereof, wherein:
- X1, X2, X3, and X4 are independently amino acids;
- X1 and X2 each independently comprise a reactive moiety capable of forming a crosslink with the other, and X3 and X4 each independently comprise a reactive moiety capable of forming a crosslink with the other;
- and
- the amino acid sequence includes 1 to 9 amino acid substitutions, inclusive, at positions other than X1, X2, X3, and X4;
- provided that at least one amino acid substitution is at H7, S8, G18, or E19;
- and provided that the amino acid substitution at G18 is not G18H.
A peptide comprising the amino acid sequence:
- (SEQ ID NO:
- 2)
- G X1 G K F X2 H S K K K F G K A X3 V G E X4 A K K,
- or a pharmaceutically acceptable salt thereof, wherein:
- X1, X2, X3, and X4 are independently amino acids;
- X1 and X2 are connected via a crosslink, and X3 and X4 are connected via a crosslink;
- and
- the amino acid sequence includes 1 to 11 amino acid substitutions, inclusive, at positions other than X1, X2, X3, and X4;
- provided that at least one amino acid is substituted by W.
A peptide of comprising the amino acid sequence:
- (SEQ ID NO:
- 2)
- G X1 G K F X2 H S K K K F G K A X3 V G E X4 A K K,
- or a pharmaceutically acceptable salt thereof, wherein:
- X1, X2, X3, and X4 are independently amino acids;
- X1 and X2 each independently comprise a reactive moiety capable of forming a crosslink with the other, and X3 and X4 each independently comprise a reactive moiety capable of forming a crosslink with the other;
- and
- the amino acid sequence includes 1 to 11 amino acid substitutions, inclusive, at positions other than X1, X2, X3, and X4;
- provided that at least one amino acid is substituted by W.
A peptide comprising the amino acid sequence:
- (SEQ ID NO:
- 3)
- G X1 G K F X2 K K K K K X3 V G E X4 A K K,
- or a pharmaceutically acceptable salt thereof, wherein:
- X1, X2, X3, and X4 are independently amino acids;
- X1 and X2 are connected via a crosslink, and X3 and X4 are connected via a crosslink;
- and
- the amino acid sequence optionally includes 1 to 5 amino acid substitutions, inclusive, at positions other than X1, X2, X3, and X4.
A peptide comprising the amino acid sequence:
- (SEQ ID NO:
- 3)
- G X1 G K F X2 K K K K K X3 V G E X4 A K K,
- or a pharmaceutically acceptable salt thereof, wherein:
- X1, X2, X3, and X4 are independently amino acids;
- X1 and X2 each independently comprise a reactive moiety capable of forming a crosslink with the other, and X3 and X4 each independently comprise a reactive moiety capable of forming a crosslink with the other;
- and
- the amino acid sequence optionally includes 1 to 5 amino acid substitutions, inclusive, at positions other than X1, X2, X3, and X4.
A peptide comprising the amino acid sequence:
- (SEQ ID NO:
- 101)
- Z X1 G K F X2 H S A K K F G K A F V,
- or a pharmaceutically acceptable salt thereof, wherein:
- X1 and X2 are independently amino acids;
- X1 and X2 are connected via a crosslink;
- and
- the amino acid sequence optionally includes 1 to 5 amino acid substitutions, inclusive, at positions other than X1 and X2.
A peptides comprising the amino acid sequence:
- (SEQ ID NO:
- 101)
- Z X1 G K F X2 H S A K K F G K A F V,
- or a pharmaceutically acceptable salt thereof, wherein:
- X1 and X2 are independently amino acids;
- X1 and X2 each independently comprise a reactive moiety capable of forming a crosslink with the other;
- and
- the amino acid sequence optionally includes 1 to 5 amino acid substitutions, inclusive, at positions other than X1 and X2.
The peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the crosslinks are attached to the α-positions of the amino acids X1, X2, X3, and X4.
The peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each crosslink is independently optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted acylene, or any combination thereof.
The peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each crosslink is independently of the following formula:
- wherein each n is independently an integer from 1-10, inclusive.
The peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, and X4 are independently α,α-disubstituted amino acids.
The peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1 and X2, and X3 and X4, are each independently connected by a crosslink to form the following formula:
- wherein α denotes the α-carbons of the amino acids;
- and wherein each instance of R1 is independently optionally substituted C1-6 alkyl.
The peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1 and X2, and X3 and X4, are each connected by a crosslink to form the following formula:
- wherein α denotes the α-carbons of the amino acids.
The peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each crosslink is independently about 10 Å to about 16 Å in length, inclusive.
The peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the length of each crosslink is approximately equal to the length of 5 to 13 carbon-carbon bonds, inclusive.
The peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one crosslink spans at least one turn of an α-helix of the peptide.
The peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, and X4 independently comprise α-sidechains comprising the reactive moieties.
The peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the reactive moieties are independently selected from alkenes and alkynes.
The peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, and X4 independently comprise α-sidechains of the following formula:
- wherein each n is independently an integer from 1-10, inclusive.
The peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, and X4 are independently α,α-disubstituted amino acids.
The peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each instance of X1, X2, X3, and X4 is an amino acid of the formula:
A method of preparing a crosslinked peptide of any one of the preceding claims comprising a step of reacting an uncrosslinked peptide of any one of the preceding claims under conditions sufficient to form the crosslinks connecting X1 and X2, and X3 and X4.
A formulation comprising a stapled antimicrobial peptide (StAMP) and one or more lipids.
Dependencies are inferred from the claim text.