Stapled intracellular-targeting antimicrobial peptides to treat infection
AssigneeDana-Farber Cancer Institute, Inc.
InventorsLoren D. Walensky, Rida Mourtada
Life of this patent
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Abstract
Structurally stabilized, e.g., stapled, peptides with the ability to translocate through microbial cell membranes to the interior of microbial cells and exert a biological activity there are provided, as are methods of designing, making and using such peptides.
Claims27
A stapled peptide or a pharmaceutically acceptable salt thereof comprising the amino acid sequence TRSSRAGLQWPVGRVX1RLLX2K (SEQ ID NO:38), TRSSRAGLQWPX1GRVX2RLLRK (SEQ ID NO:42), TRSSRAGLX1WPVX2RVHRLLRK (SEQ ID NO:43), TRX1SRAX2LQWPVGRVHRLLRK (SEQ ID NO:47), TRSSRAX3LQWPVGX4VHRLLRK (SEQ ID NO:55), or TRSSX3AGLQWPX4GRVHRLLRK (SEQ ID NO:57),
- wherein each of X1, X2, X3, and X4 is a non-natural amino acid,
- wherein X1 and X2 are cross-linked to each other where present, and
- wherein X3 and X4 are cross-linked to each other where present.
A method of making a stapled peptide or pharmaceutically acceptable salt thereof, the method comprising:
- (a) providing a peptide comprising the amino acid sequence:
- TRSSRAGLQWPVGRVX1RLLX2K (SEQ ID NO:38), TRSSRAGLQWPX1GRVX2RLLRK (SEQ ID NO:42), TRSSRAGLX1WPVX2RVHRLLRK (SEQ ID NO:43), TRX1SRAX2LQWPVGRVHRLLRK (SEQ ID NO:47), TRSSRAX3LQWPVGX4VHRLLRK (SEQ ID NO:55), or TRSSX3AGLQWPX4GRVHRLLRK (SEQ ID NO:57), wherein each of X1, X2, X3, and X4 is an α, α-disubstituted non-natural amino acid comprising an olefinic side chain;
- and
- (b) performing a ring-closing metathesis reaction on the peptide, thereby making the stapled peptide.
Dependencies are inferred from the claim text.