| US 7,517,849 B1 | ||
| Inhibition of ABC transporters by transmembrane domain analogs | ||
| Nadya I. Tarasova, Frederick, Md. (US); Christopher J. Michejda, North Potomac, Md. (US); Michael M. Gottesman, Bethesda, Md. (US); and Christine A. Hrycyna, Lafayette, Ind. (US) | ||
| Assigned to The United States of America as represented by the Secretary of Health and Human Services, Washington, D.C. (US) | ||
| Appl. No. 10/130,192 PCT Filed Nov. 17, 2000, PCT No. PCT/US00/31817 § 371(c)(1), (2), (4) Date May 13, 2002, PCT Pub. No. WO01/36477, PCT Pub. Date May 25, 2001. |
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| Claims priority of provisional application 60/166767, filed on Nov. 22, 1999. | ||
| Claims priority of provisional application 60/166382, filed on Nov. 18, 1999. | ||
| Int. Cl. A61K 38/00 (2006.01); C07K 5/00 (2006.01); G01N 33/53 (2006.01); C07K 14/00 (2006.01) | ||
| U.S. Cl. 514—2 [530/300; 530/350; 435/7.1; 435/7.2] | 39 Claims |
| 1. An isolated ATP-binding cassette (ABC) transporter protein-inhibiting peptide, wherein
(a) said ABC transporter protein comprises a sequence of amino acid residues which forms a plurality of transmembrane domains
and extracellular domains when said protein is present in a cell plasma membrane,
(b) said ABC transporter protein-inhibiting peptide has a first end and a second end, and said peptide has at said first end
a group that is negatively charged under physiological conditions and at said second end has a group that is neutrally charged
under physiological conditions;
(c) said first end comprises 1 to 6 amino acid residues, of which at least 1 is negatively charged at physiological pH;
(d) said second end consists of a sequence of amino acid residues, which sequence (i) consists of the sequence of amino acid
residues of a transmembrane domain of said ABC transporter protein, and, optionally, further comprises between said first
and second ends, one or more residues from the amino acid residue sequence of the extracellular domain of said ABC transporter
protein directly adjacent to said transmembrane domain, (ii) consists of the sequence of ten or more amino acid residues of
said transmembrane domain and, optionally, further comprises between said first and second ends, one or more residues from
the amino acid residue sequence of the extracellular domain of said ABC transporter protein directly adjacent to said transmembrane
domain or, (iii) consists of a sequence with at least 90% sequence identity to the sequence of (i) or (ii);
(e) said peptide spontaneously inserts into a plasma membrane of a cell in the same orientation as the ABC transporter protein
transmembrane domain with which it shares sequence identity when said ABC transporter protein is present in said plasma membrane
of said cell; and
(f) said peptide inhibits efflux of a substrate of said ABC transporter protein from cells expressing said ABC transporter
protein when said cells are contacted with said peptide.
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