POTENT AND SELECTIVE INHIBITORS OF NAV1.7

摘要

Disclosed is a composition of matter comprising an isolated polypeptide, which is a peripherally-restricted NaV1.7 inhibitor. In some disclosed embodiments, the isolated polypeptide is an inhibitor of NaV1.7. Other embodiments are conjugated embodiments of the inventive composition of matter and pharmaceutical compositions containing the inventive composition of matter. Isolated nucleic acids encoding some embodiments of inventive polypeptides and expression vectors, and recombinant host cells containing them are disclosed. A method of treating or preventing pain is also disclosed.

主权项

1. A composition of matter comprising an isolated polypeptide comprising the amino acid sequence of the formula:
Xaa1Xaa2Xaa3Xaa4Xaa5Xaa6Xaa7Xaa8Xaa9Xaa10Xaa11Aspaa12Xaa13Xaa14Xaa15Xaa16Xaa17Xaa18Xaa19Xaa20Leuaa21Xaa22Xaa23Xaa24Xaa25Xaa26Xaa27Xaa28Xaa29Xaa30Xaa31Xaa32Xaa33Xaa34//SEQ ID NO:590or a pharmaceutically acceptable salt thereof,wherein:
Xaa1Xaa2 is absent; or Xaa1 is any amino acid residue and Xaa2 is any amino acid residue; or Xaa1 is absent and Xaa2 is any amino acid residue; or Xaa1 is absent and Xaa2 is absent; Xaa3 is any amino acid residue; Xaa4 is Cys, if Xaa18 is Cys; or Xaa4 is SeCys, if Xaa18 is SeCys; Xaa5 is any neutral hydrophilic or basic amino acid residue; Xaa6 is any basic or neutral hydrophilic amino acid residue; Xaa7 is a Trp, 5-bromoTrp, 6-bromoTrp, 5-chloroTrp, 6-chloroTrp, 1-Nal, 2-Nal, thioTrp, BhPhe, 2-BrhF, 2-C1hF, 2-FhF, 2-MehF, 2-MeOhF, 3-BrhF, 3-C1hF, 3-FhF, 3-MehF, 3-MeOhF, 4-BrhF, 4-C1hF, 4-FhF, 4-Me-F, 4-MehF, 4-MeOhF residue; Xaa8 is a Met, Nle, Nva, Leu, Ile, Val, or Phe residue; Xaa9 is a Trp, 5-bromoTrp, 6-bromoTrp, 5-chloroTrp, 6-chloroTrp, 1-Nal, 2-Nal, or thioTrp residue; Xaa10 is a basic or neutral hydrophilic amino acid residue, or an Ala residue; Xaa11 is Cys if Xaa23 is Cys; or Xaa11 is SeCys if Xaa23 is SeCys; Xaa13 is any amino acid residue; Xaa14 is a basic or acidic residue or an Ala residue; Xaa15 is an Arg or Cit residue; Xaa16 is any amino acid residue; Xaa17 is a Cys if Xaa27 is Cys; or Xaa17 is a SeCys if Xaa27 is SeCys; Xaa18 is a Cys or SeCys; Xaa19 is any amino acid residue; Xaa20 is a Gly, Asp or Ala residue; Xaa22 is an acidic, basic, or neutral hydrophilic amino acid residue, or Ala or Val residue; Xaa23 is a Cys or SeCys residue; Xaa24 is a basic or neutral hydrophilic amino acid or Ala residue; Xaa25 is an aliphatic hydrophobic residue; Xaa26 is a Trp, 5-bromoTrp, 6-bromoTrp, 5-chloroTrp, 6-chloroTrp, 7-BrW, 1-Nal, 2-Nal, thioTrp, 5-phenylTrp, 5-iPrTrp, 5-ethylTrp, or 5-MeTrp residue; Xaa27 is a Cys or SeCys residue; Xaa28 is a basic or neutral hydrophilic amino acid residue; Xaa29 is a basic amino acid residue, or a Tyr or Leu residue; Xaa30 is an Ile, Trp, Tyr, 5-bromoTrp, 6-bromoTrp, 5-chloroTrp, 6-chloroTrp, thioTrp, 1-Nal, or 2-Nal residue, if Xaa22 is an acidic amino acid residue; or Xaa30 is an acidic amino acid residue or a Pro residue, if Xaa22 is a basic or neutral hydrophilic amino acid residue or an Ala or Val residue; Xaa31 is an Ile, Trp, Phe, BhPhe, Cha, Tyr, 5-bromoTrp, 6-bromoTrp, 5-chloroTrp, 6-chloroTrp, 1-Nal, 2-Nal, thioTrp, or 4-tBu-F residue; each of Xaa32, Xaa33, and Xaa34 is independently absent or is independently a hydrophobic or acidic amino acid residue, or a Ser or Gly residue; and wherein: if Xaa4 and Xaa18 are both Cys residues, there is a disulfide bond between residue Xaa4 and residue Xaa18; or if Xaa4 and Xaa18 are both SeCys residues, there is a diselenide bond between residue Xaa4 and residue Xaa18; if Xaa11 and Xaa23 are both Cys residues, there is a disulfide bond between residue Xaa1 and residue Xaa23; or if Xaa11 and Xaa23 are both SeCys residues, there is a diselenide bond between residue Xaa11 and residue Xaa23; if Xaa17 and Xaa27 are both Cys residues, there is a disulfide bond between residue Xaa17 and residue Xaa27; or if Xaa17 and Xaa27 are both SeCys residues, there is a diselenide bond between residue Xaa17 and residue Xaa27; the amino-terminal residue is optionally acetylated, biotinylated, or 4-pentynoylated, or PEGylated; and the carboxy-terminal residue is optionally amidated.