Ras inhibitory peptides and uses thereof
AssigneePresident and Fellows of Harvard College
InventorsGregory L. Verdine, John Hanney McGee
Life of this patent
Estimating the term…
Abstract
The present invention provides peptides comprising a sequence of X-6X-5X-4X-3X-2X-1X1PX3X4PX6X7PGX10X11AX13X14X15X16LX18X19X20X21X22X23LX25X26YLX29X30X31X32 (SEQ ID NO: 13) wherein the amino acids X−6, X−5, X−4, X−3, X−2, X−1, X1, X3, X4, X6, X7, X10, X11, X13, X14, X15, X16, X18, X19, X20, X21, X22, X25, X26, X29, X30, X31, and X32 are as defined herein. The present invention further provides pharmaceutical compositions comprising the peptides and methods of using the peptides for treating proliferative diseases such as cancer which are associated with Ras. Also provided are methods of screening a library of peptide dimers using a peptide dimer display technology.
Claims12
A peptide comprising an oligomerization domain comprising a sequence of:
- (SEQ ID NO:
- 2)
- PXaXbPXcXdP,
- wherein each of Xa and Xb is independently any non-proline amino acid, and each of Xc and Xa is independently an amino acid capable of cross-linking the peptide with a second peptide, wherein Xa is covalently cross-linked to the second peptide.
A peptide comprising an oligomerization domain comprising a sequence of:
- (SEQ ID NO:
- 2)
- PXaXbPXcXdP,
- wherein each of Xa, Xb, and Xc is independently any non-proline amino acid, and Xa is an amino acid covalently cross-linked to a second peptide, wherein the second peptide comprises a sequence of:
- PXaXbPXcXdP (SEQ ID NO:
- 2).
A peptide comprising an oligomerization domain comprising a sequence of:
- PXaXbPXcXdP (SEQ ID NO:
- 2),
- wherein each of Xa, Xb, and Xc is independently any non-proline amino acid, and Xa is an amino acid covalently cross-linked to a second peptide, further comprising an alpha-helical domain comprising a sequence of:
- (SEQ ID NO:
- 100)
- X13X14X15DLX18X19YX21X22RLX25X26YLX29X30VA,
- wherein
- X13 is Ser, Pro, Thr, or an amino acid capable of cross-linking the peptide with another peptide;
- X14 is Ile, Glu, Val, Leu, or an amino acid capable of cross-linking the peptide with another peptide;
- X15 is Glu, Lys, Arg, Ala, Ser, Asp, Gln, or Gly;
- X18 is an aromatic or hydrophobic amino acid;
- X19 is Glu, Lys, Leu, Met, His, Asp, Gln, Ala, Ser, Trp, or Arg;
- X21 is Gln, Tyr, Phe, Trp, His, or an amino acid with a cyclohexyl side chain, wherein Tyr, Phe, Trp, or the cyclohexyl side chain can be substituted with one or more fluorines;
- X22 is Ala, Gln, Trp, Leu, Tyr, Gly, Ser, Val, or Asn;
- X25 is Gln, Tyr, Phe, Trp, His, Asp, or an amino acid with a cyclohexyl side chain, wherein Tyr, Phe, Trp, or the cyclohexyl side chain can be substituted with one or more fluorines;
- X26 is Asn, Ala, Leu, Arg, Phe, Ile, His, or Gln;
- X29 is Ala, Leu, Glu, Asn, Gln, Tyr, Phe, Trp, His, or an amino acid with a cyclohexyl side chain, wherein Tyr, Phe, Trp, or the cyclohexyl side chain can be substituted with one or more fluorines and
- X30 is Ala, Arg or Val.
A peptide comprising an oligomerization domain comprising a sequence of:
- (SEQ ID NO:
- 2)
- PXaXbPXcXdP,
- wherein each of Xa, Xb, and Xc is independently any non-proline amino acid, and Xd is an amino acid covalently cross-linked to a second peptide, wherein Xd is Cys, Sec, Phe, Trp, or Tyr.
A peptide comprising an oligomerization domain comprising a sequence of:
- (SEQ ID NO:
- 2)
- PXaXbPXcXdP,
- wherein each of Xa, Xb, and Xc is independently any non-proline amino acid, and Xd is an amino acid covalently cross-linked to a second peptide, wherein the peptide comprising an oligomerization domain has a sequence of:
- PRRPRCPGHAASIAALHAYWARLWNYLYRVR (SEQ ID NO:
- 42).
A peptide comprising an oligomerization domain comprising a sequence of:
- (SEQ ID NO:
- 2)
- PXaXbPXcXdP,
- wherein each of Xa, Xb, and Xc is independently any non-proline amino acid, and Xd is an amino acid covalently cross-linked to a second peptide, wherein Xd is not Cys.
Dependencies are inferred from the claim text.