Polyphoshoinositide binding peptides for intracellular drug delivery
First Claim
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1. 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;
space="preserve" listing-type="equation">X-P,whereinP 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.
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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.
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Citations
60 Claims
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1. A compound comprising:
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(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;
space="preserve" listing-type="equation">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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)
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21. A compound comprising:
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(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;
space="preserve" listing-type="equation">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. - View Dependent Claims (22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)
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41. A compound comprising:
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(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;
space="preserve" listing-type="equation">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. - View Dependent Claims (42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60)
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Specification