Polyphoshoinositide binding peptides for intracellular drug delivery
AssigneeThe Brigham and Women's Hospital, Inc.
InventorsPaul A. Janmey, C. Casey Cunningham, John H. Hartwig, Thomas P. Stossel, Roland Vegner
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Abstract
Methods and compositions for facilitating the transport of a membrane-impermeable extracellular agent having an intracellular activity across the membrane of a cell are provided. The methods involve covalently coupling an amino terminal blocking group to a transport-mediating peptide to form a carrier molecule. The carrier molecule is covalently coupled to the extracellular agent to form a membrane-permeable prodrug. The transport-mediating peptides are highly basic and bind to polyphosphoinositides.
Claims60
A compound comprising:
- (i) a carrier molecule for facilitating the transport of a membrane-impermeable extracellular agent having an intracellular activity across a membrane of a cell, the carrier molecule having the formula:
- X-P,
- wherein
- P is a transport-mediating peptide selected from the group consisting of Seq. I.D. Nos. 1-35 and 36;
- and X is a terminal amine derivatizing agent that is covalently coupled to the N-terminus amine of the transport-mediating peptide,
- wherein each of the functionally equivalent peptides is a basic polyphosphoinositide binding peptide containing between three and ten amino acids, and
- (ii) a membrane-impermeable extracellular agent, A, covalently coupled to the carboxyl terminus of the transport-mediating peptide to form a prodrug having the formula, X-P-A.
A compound comprising:
- (i) a carrier molecule for facilitating the transport of a membrane-impermeable extracellular agent having an intracellular activity across a membrane of a cell, the carrier molecule having the formula:
- X-P,
- wherein
- P is a transport-mediating peptide that is a peptide fragment of a peptide selected from the group consisting of Seq. I.D. No. 1 and Seq. I.D. No.2, wherein the peptide fragment is a basic polyphosphoinositide binding peptide and contains between three and ten amino acids, and X is a terminal amine derivatizing agent that is covalently coupled to the N-terminus amine of the transport-mediating peptide,
- (ii) a membrane-impermeable extracellular agent, A, covalently coupled to the carboxyl terminus of the transport-mediating peptide to form a compound having the formula, X-P-A.
A compound comprising:
- (i) a carrier molecule for facilitating the transport of a membrane-impermeable extracellular agent having an intracellular activity across a membrane of a cell, the carrier molecule having the formula:
- X-P,
- wherein
- P is a transport-mediating peptide that is a polyphosphoinositide binding peptide comprising between three and ten amino acids of a polyphosphoinositide domain of a polyphosphoinositide binding protein, wherein the polyphosphoinositide domain comprises a sequence selected from the group consisting of (K/R)xxx(K/R)x(K/R)(K/R) and (K/R)xxxx(K/R)x(K/R)(K/R), SEQ. ID. NO. 37 and SEQ. ID. NO:38, respectively wherein (K/R) represents lysine or arginine and x represents a neutral amino acid;
- and X is a terminal amine derivatizing agent that is covalently coupled to the N-terminus amine of the transport-mediating peptide,
- (ii) a membrane-impermeable extracellular agent, A, covalently coupled to the carboxyl terminus of the transport-mediating peptide to form a compound having the formula, X-P-A.
Dependencies are inferred from the claim text.