Cell-penetrating peptides, conjugates thereof, and methods of their use
AssigneePepgen Corporation
InventorsAshling HOLLAND, Smita GUNNOO, Robert HAMMER, Niels SVENSTRUP, Caroline GODFREY, Sonia BRACEGIRDLE
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Abstract
Disclosed are peptides and conjugates of the peptide covalently bonded or linked via a linker to a therapeutic or diagnostic molecule, the peptide including at least one cationic domain and at least one hydrophobic domain.
Claims117
A conjugate comprising a peptide and a therapeutic or diagnostic molecule covalently bonded or linked via a non-cationic linker to the peptide,
- the peptide comprising a total of one hydrophobic domain and a total of one cationic domain, the cationic domain comprising at least 1 cationic amino acid residue, and the hydrophobic domain comprising at least 3 amino acid residues, provided that the peptide comprises a total of 5 to 40 (e.g., 6 to 40 or 7 to 40) amino acid residues and does not comprise any artificial amino acid residues.
A conjugate comprising a peptide and a therapeutic or diagnostic molecule covalently bonded or linked via a non-cationic linker to the peptide,
- the peptide comprising a total of one hydrophobic domain and a total of one or two cationic domains flanking the hydrophobic domain, each cationic domain comprising at least one cationic amino acid residue, at least one of the cationic domains comprising a total of one cationic amino acid residue, and the hydrophobic domain comprising at least 3 amino acid residues, provided that the peptide comprises a total of 5 to 40 (e.g., 6 to 40 or 7 to 40) amino acid residues and does not comprise any artificial amino acid residues, wherein the amino acid residues for each cationic domain are selected from the group consisting of arginine, histidine, and beta-alanine.
A conjugate comprising a peptide and a therapeutic or diagnostic molecule covalently bonded or linked via a non-cationic linker to the peptide,
- the peptide comprising a total of one hydrophobic domain and a total of one or two cationic domains flanking the hydrophobic domain, each cationic domain comprising at least 1 cationic amino acid residue, all cationic domains collectively comprising a total of five or fewer cationic amino acid residues, and the hydrophobic domain comprising at least 3 amino acid residues, provided that the peptide comprises a total of 5 to 40 (e.g., 6 to 40 or 7 to 40) amino acid residues and does not comprise any artificial amino acid residues, wherein the amino acid residues for each cationic domain are selected from the group consisting of arginine, histidine, and beta-alanine.
A conjugate comprising a peptide and a therapeutic or diagnostic molecule covalently bonded or linked via a non-cationic linker to the peptide,
- the peptide comprising a total of one hydrophobic domain and a total of one or two cationic domains flanking the hydrophobic domain, each cationic domain comprising at least 1 cationic amino acid residue, at least one third of amino acid residues in the N-terminal cationic domain are histidines, and the hydrophobic domain comprising at least 3 amino acid residues, provided that the peptide comprises a total of 5 to 40 (e.g., 6 to 40 or 7 to 40) amino acid residues and does not comprise any artificial amino acid residues.
The conjugate of any preceding claim, wherein each cationic domain comprises at least 40%, at least 45%, or at least 50% cationic amino acids.
The conjugate of any preceding claim, wherein each cationic domain comprises a majority of cationic amino acids, preferably at least at least 55%, at least 60%, at least 65% at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% cationic amino acids.
The conjugate of any preceding claim, wherein each cationic domain is arginine rich and/or histidine rich, preferably each cationic domain comprises at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 60%, at least 65%, or least 70% arginine and/or histidine residues.
The conjugate of any preceding claim, wherein each hydrophobic domain has a length of between 3-6 amino acids, preferably each hydrophobic domain has a length of 5 amino acids.
The conjugate of any preceding claim, wherein each hydrophobic domain comprises a majority of hydrophobic amino acid residues, preferably each hydrophobic domain comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% hydrophobic amino acids.
The conjugate of any preceding claim, wherein each hydrophobic domain comprises phenylalanine, leucine, isoleucine, tyrosine, tryptophan, proline, and/or glutamine residues;
- preferably wherein each hydrophobic domain consists of phenylalanine, leucine, isoleucine, tyrosine, tryptophan, proline, and/or glutamine residues, provided at least one of phenylalanine, leucine, isoleucine, tyrosine, and tryptophan is present.
The conjugate of any preceding claim, wherein the hydrophobic domain is FQILY (SEQ ID NO:
- 446).
A conjugate of a peptide and a therapeutic or diagnostic molecule covalently bonded or linked via a non-cationic linker to the peptide,
- the peptide being selected from the group consisting of:
- RBRRFQILYRBHBH (SEQ ID NO:
- 447), RBRFQILYRBHBH (SEQ ID NO:
- 448), RBFQILYRBHBH (SEQ ID NO:
- 449), RFQILYRBHBH (SEQ ID NO:
- 450), FQILYRBHBH (SEQ ID NO:
- 451), RBRRBRRFQILYBHBHB (SEQ ID NO:
- 452), RBRRBRRFQILYHBH (SEQ ID NO:
- 453), RBRRBRRFQILYBH (SEQ ID NO:
- 454), RBRRBRRFQILYH (SEQ ID NO:
- 455), RBRRBRRFQILY (SEQ ID NO:
- 456), BRRBRRFQILYRBHBH (SEQ ID NO:
- 457), RRBRRFQILYRBHBH (SEQ ID NO:
- 458), BRRFQILYRBHBH (SEQ ID NO:
- 459), RRFQILYRBHBH (SEQ ID NO:
- 460), RBRRBRRFQILYRBHB (SEQ ID NO:
- 461), RBRRBRRFQILYRBH (SEQ ID NO:
- 462), RBRRBRRFQILYRB (SEQ ID NO:
- 463), RBRRBRRFQILYR (SEQ ID NO:
- 464), HRBHRBHRBFQILYHRBRH (SEQ ID NO:
- 465), HRBHRBHRBFQILYHRBHRBHR (SEQ ID NO:
- 466), HRBHRBFQILYHRBHR (SEQ ID NO:
- 467), HRBFQILYHR (SEQ ID NO:
- 468), RBRBRBFQILYRBRBR (SEQ ID NO:
- 469), RBRBFQILYRBR (SEQ ID NO:
- 470), RBFQILYR (SEQ ID NO:
- 471), HRHRHRFQILYHRHRHR (SEQ ID NO:
- 472), HRHRFQILYHRHR (SEQ ID NO:
- 473), HRFQILYHR (SEQ ID NO:
- 474), RRRRRRFQILY (SEQ ID NO:
- 475), FQILYRRRRRR (SEQ ID NO:
- 476), RRRRRRFQILYRRRRRR (SEQ ID NO:
- 477), RBRRBRFQILYBR (SEQ ID NO:
- 478), and RBRRBRFQILY (SEQ ID NO:
- 479).
A conjugate of a peptide and a therapeutic or diagnostic molecule covalently bonded or linked via a non-cationic linker to the peptide,
- The peptide being selected from the group consisting of:
- RBRRFQILYRBHBHB (SEQ ID NO:
- 481), RBRFQILYRBHBHB (SEQ ID NO:
- 482), RBFQILYRBHBHB (SEQ ID NO:
- 483), RFQILYRBHBHB (SEQ ID NO:
- 484), FQILYRBHBHB (SEQ ID NO:
- 485), RBRRBRRFQILYBHBHB (SEQ ID NO:
- 452), RBRRBRRFQILYHBHB (SEQ ID NO:
- 486), RBRRBRRFQILYBHB (SEQ ID NO:
- 487), RBRRBRRFQILYHB (SEQ ID NO:
- 488), RBRRBRRFQILYB (SEQ ID NO:
- 489), RBRRBRRFQILYE (SEQ ID NO:
- 416), RBRRBRRFQILY (SEQ ID NO:
- 456), BRRBRRFQILYRBHBHB (SEQ ID NO:
- 490), RRBRRFQILYRBHBHB (SEQ ID NO:
- 491), BRRFQILYRBHBHB (SEQ ID NO:
- 492), RRFQILYRBHBHB (SEQ ID NO:
- 493), RRFQILYRBHBHE (SEQ ID NO:
- 417), RBRRBRRFQILYRBHBB (SEQ ID NO:
- 494), RBRRBRRFQILYRBHB (SEQ ID NO:
- 461), RBRRBRRFQILYRBB (SEQ ID NO:
- 495), RBRRBRRFQILYRB (SEQ ID NO:
- 463), HRBHRBHRBFQILYHRBRHB (SEQ ID NO:
- 496), HRBHRBHRBFQILYHRBHRBHRB (SEQ ID NO:
- 497), HRBHRBFQILYHRBHRB (SEQ ID NO:
- 498), HRBFQILYHRB (SEQ ID NO:
- 499), RBRBRBFQILYRBRBRB (SEQ ID NO:
- 500), RBRBFQILYRBRB (SEQ ID NO:
- 501), RBFQILYRB (SEQ ID NO:
- 502), HRHRHRFQILYHRHRHRB (SEQ ID NO:
- 503), HRHRFQILYHRHRB (SEQ ID NO:
- 504), HRFQILYHRB (SEQ ID NO:
- 505), RRRRRRFQILYB (SEQ ID NO:
- 506), FQILYRRRRRRB (SEQ ID NO:
- 507), RRRRRRFQILYRRRRRRB (SEQ ID NO:
- 508), RBRRBRFQILYBRE (SEQ ID NO:
- 415), and RBRRBRFQILYE (SEQ ID NO:
- 509).
The conjugate of any preceding claim, wherein the peptide is bonded to the rest of the conjugate through its N-terminus.
The conjugate of any preceding claim, wherein the peptide is covalently bonded to the therapeutic or diagnostic molecule.
The conjugate of any preceding claim, wherein the therapeutic or diagnostic molecule comprises an oligonucleotide that is optionally bonded to the linker or the peptide at its 3′ terminus.
A peptide comprising a total of one hydrophobic domain and a total of one cationic domain, the cationic domain comprising at least 1 cationic amino acid residue, and the hydrophobic domain comprising at least 3 amino acid residues, provided that the peptide comprises a total of 5 to 40 amino acid residues and does not comprise any artificial amino acid residues.
A peptide comprising a total of one hydrophobic domain and a total of one or two cationic domains flanking the hydrophobic domain, each cationic domain comprising at least one cationic amino acid residue, at least one of the cationic domains comprising a total of one cationic amino acid residue, and the hydrophobic domain comprising at least 3 amino acid residues, provided that the peptide comprises a total of 5 to 40 amino acid residues and does not comprise any artificial amino acid residues, wherein the amino acid residues for each cationic domain are selected from the group consisting of arginine, histidine, and beta-alanine.
A peptide comprising a total of one hydrophobic domain and a total of one or two cationic domains flanking the hydrophobic domain, each cationic domain comprising at least 1 cationic amino acid residue, all cationic domains collectively comprising a total of five or fewer cationic amino acid residue, and the hydrophobic domain comprising at least 3 amino acid residues, provided that the peptide comprises a total of 5 to 40 amino acid residues and does not comprise any artificial amino acid residues, wherein the amino acid residues for each cationic domain are selected from the group consisting of arginine, histidine, and beta-alanine.
A peptide comprising a total of one hydrophobic domain and a total of one or two cationic domains flanking the hydrophobic domain, each cationic domain comprising at least 1 cationic amino acid residue, at least one third of amino acid residues in the N-terminal cationic domain are histidines, and the hydrophobic domain comprising at least 3 amino acid residues, provided that the peptide comprises a total of 5 to 40 amino acid residues and does not comprise any artificial amino acid residues.
A peptide selected from the group consisting of:
- RBRRFQILYRBHBHB (SEQ ID NO:
- 481), RBRFQILYRBHBHB (SEQ ID NO:
- 482), RBFQILYRBHBHB (SEQ ID NO:
- 483), RFQILYRBHBHB (SEQ ID NO:
- 484), FQILYRBHBHB (SEQ ID NO:
- 485), RBRRBRRFQILYBHBHB (SEQ ID NO:
- 452), RBRRBRRFQILYHBHB (SEQ ID NO:
- 486), RBRRBRRFQILYBHB (SEQ ID NO:
- 487), RBRRBRRFQILYHB (SEQ ID NO:
- 488), RBRRBRRFQILYB (SEQ ID NO:
- 489), RBRRBRRFQILYE (SEQ ID NO:
- 416), RBRRBRRFQILY (SEQ ID NO:
- 456), BRRBRRFQILYRBHBHB (SEQ ID NO:
- 490), RRBRRFQILYRBHBHB (SEQ ID NO:
- 491), BRRFQILYRBHBHB (SEQ ID NO:
- 492), RRFQILYRBHBHB (SEQ ID NO:
- 493), RRFQILYRBHBHE (SEQ ID NO:
- 417), RBRRBRRFQILYRBHBB (SEQ ID NO:
- 494), RBRRBRRFQILYRBHB (SEQ ID NO:
- 461), RBRRBRRFQILYRBB (SEQ ID NO:
- 495), RBRRBRRFQILYRB (SEQ ID NO:
- 463), HRBHRBHRBFQILYHRBRHB (SEQ ID NO:
- 496), HRBHRBHRBFQILYHRBHRBHRB (SEQ ID NO:
- 497), HRBHRBFQILYHRBHRB (SEQ ID NO:
- 498), HRBFQILYHRB (SEQ ID NO:
- 499), RBRBRBFQILYRBRBRB (SEQ ID NO:
- 500), RBRBFQILYRBRB (SEQ ID NO:
- 501), RBFQILYRB (SEQ ID NO:
- 502), HRHRHRFQILYHRHRHRB (SEQ ID NO:
- 503), HRHRFQILYHRHRB (SEQ ID NO:
- 504), HRFQILYHRB (SEQ ID NO:
- 505), RRRRRRFQILYB (SEQ ID NO:
- 506), FQILYRRRRRRB (SEQ ID NO:
- 507), RRRRRRFQILYRRRRRRB (SEQ ID NO:
- 508), RBRRBRFQILYBRE (SEQ ID NO:
- 415), and RBRRBRFQILYE (SEQ ID NO:
- 509).
A peptide comprising or consisting of rBrrBrfqilyBrBr (SEQ ID NO:
- 510) or rBrrBrfqilyBrBre (SEQ ID NO:
- 513), where lower case letters indicate D-amino acids.
A peptide comprising or consisting of the sequence of SEQ ID NO:
- 415, 509, 416, 417, 418, 402, 512, 403, 404, 405, 478, 479, 456, or 460.
Dependencies are inferred from the claim text.