PEPTIDE COMPOSITIONS AND METHODS OF USE THEREOF FOR DISRUPTING TEAD INTERACTIONS
Described herein are peptides and variants and mutants thereof capable of interacting with TEAD, disrupting the HIPPO pathway, or modulating the activity or function of TEAD interactions in a cell. Pharmaceutical compositions and uses of peptides, as well as methods of designing and manufacturing such peptides, to treat cancer, tumor, or any other disease/condition associated with a dysregulated HIPPO pathway or uncontrolled cell growth are also described herein.
1 - 151 . (canceled)
152 . A composition comprising a non-naturally occurring transcriptional enhanced associate domain (TEAD)-binding peptide, wherein the TEAD-binding peptide comprises:
an LX 1 X 2 LF motif,
a tryptophan amino acid residue positioned 4 residues N-terminal of the LX 1 X 2 LF motif;
at least six cysteine amino acid residues comprising:
a first cysteine amino acid residue positioned 16 residues N-terminal of the LX 1 X 2 LF motif,
a second cysteine amino acid residue positioned 15 residues N-terminal of the LX 1 X 2 LF motif,
a third cysteine amino acid residue positioned 9 residues N-terminal of the LX 1 X 2 LF motif,
a fourth cysteine amino acid residue positioned 2 residues N-terminal of the LX 1 X 2 LF motif,
a fifth cysteine amino acid residue positioned 8 residues C-terminal of the LX 1 X 2 LF motif,
a sixth cysteine amino acid residue positioned 12 residues N-terminal of the LX 1 X 2 LF motif, and
two or more disulfide bridges formed between the at least six cysteine amino acid residues.
153 . The composition of claim 152 , wherein:
the first cysteine amino acid residue is positioned 17 residues N-terminal of X 1 of the LX 1 X 2 LF motif,
the second cysteine amino acid residue is positioned 16 residues N-terminal of X 1 of the LX 1 X 2 LF motif,
the third cysteine amino acid residue is positioned 10 residues N-terminal of X 1 of the LX 1 X 2 LF motif,
the fourth cysteine amino acid residue is positioned 3 residues N-terminal of X 1 of the LX 1 X 2 LF motif,
the fifth cysteine amino acid residue is positioned 11 residues C-terminal of X 1 of the LX 1 X 2 LF motif,
the sixth cysteine amino acid residue is positioned 15 residues N-terminal of X 1 of the LX 1 X 2 LF motif.
154 . The composition of claim 152 , wherein the tryptophan amino acid residue is positioned 5 residues N-terminal of X 1 of the LX 1 X 2 LF motif.
155 . composition of claim 152 , wherein:
the first cysteine amino acid residue is positioned at residue 7 of the TEAD-binding peptide,
the second cysteine amino acid residue is positioned at residue 8 of the TEAD-binding peptide,
the third cysteine amino acid residue is positioned at residue 14 of the TEAD-binding peptide,
the fourth cysteine amino acid residue is positioned at residue 21 of the TEAD-binding peptide,
the fifth cysteine amino acid residue is positioned at residue 35 of the TEAD-binding peptide,
the sixth cysteine amino acid residue is positioned at residue 39 of the TEAD-binding peptide.
156 . The composition of claim 152 , wherein the tryptophan amino acid residue is positioned at residue 19 of the TEAD-binding peptide.
157 . The composition of claim 152 , wherein X 1 of the LX 1 X 2 LF motif is E, and wherein X 2 of the LX 1 X 2 LF motif is A.
158 . The composition of claim 152 , wherein the TEAD-binding peptide comprises a sequence having at least 80% sequence identity to SEQ ID NO: 44 or SEQ ID NO: 2.
159 . The composition of claim 152 , wherein the TEAD-binding peptide comprises a sequence of SEQ ID NO: 44 or SEQ ID NO: 2.
160 . The composition of claim 152 , further comprising a cell-penetrating moiety fused to or conjugated to the TEAD-binding peptide.
161 . The composition of claim 160 , wherein the cell-penetrating moiety is selected from the group consisting of polycations, polyorganic acids, endosomal releasing polymers, poly(2-propylacrylic acid), poly(2-ethylacrylic acid), Tat peptide, Arg patch, a knotted peptide, CysTAT, S19-TAT, R8, pAntp, Pas-TAT, Pas-R8, Pas-FHV, Pas-pAntP, F2R4 (SEQ ID NO: 152), B55, aurin, IMT-P8, BR2, OMOTAGI, OMOTAG2, pVEC, SynB3, DPV1047, C105Y, Transportan, MTS, hLF, PFVYLI, DRI-TAT, cFΦR 4 , myristate, yBBR, maurocalcin, imperatoxin, hadrucalcin, hemicalcin, opicalcin-1, opicalcin-2, midkine (62-104), MCoTI-II, and chlorotoxin, or any combination thereof.
162 . The composition of claim 160 , wherein the cell-penetrating moiety is a cell-penetrating peptide having at least 90% sequence identity with any sequence of SEQ ID NO: 143-SEQ ID NO: 176, SEQ ID NO: 280, SEQ ID NO: 281, SEQ ID NO: 286, or SEQ ID NO: 287.
163 . The composition of claim 160 , wherein the cell-penetrating moiety fused to or conjugated to the TEAD-binding peptide is a fusion peptide, and wherein the fusion peptide comprises a sequence of any one of SEQ ID NO: 222, SEQ ID NO: 85, SEQ ID NO: 231, SEQ ID NO: 94, SEQ ID NO: 232, SEQ ID NO: 95, SEQ ID NO: 256, SEQ ID NO: 119, SEQ ID NO: 257, SEQ ID NO: 120, SEQ ID NO: 258, SEQ ID NO: 121, SEQ ID NO: 259, SEQ ID NO: 122, SEQ ID NO: 260, SEQ ID NO: 123, SEQ ID NO: 261, or SEQ ID NO: 124.
164 . The composition of claim 152 , further comprising a nuclear localization signal peptide fused to or conjugated to the TEAD-binding peptide.
165 . The composition of claim 164 , wherein the nuclear localization signal peptide has at least 90% sequence identity with any sequence of SEQ ID NO: 195-SEQ ID NO: 202 or SEQ ID NO: 288.
166 . The composition of claim 152 , further comprising a pharmaceutically acceptable carrier.
167 . A method of treating a subject having a condition with a dysregulated HIPPO signaling pathway, the method comprising administering to the subject a composition comprising a non-naturally occurring transcriptional enhanced associate domain (TEAD)-binding peptide, wherein the TEAD-binding peptide comprises:
an LX 1 X 2 LF motif;
a tryptophan amino acid residue positioned 4 residues N-terminal of the LX 1 X 2 LF motif;
at least six cysteine amino acid residues comprising:
a first cysteine amino acid residue positioned 16 residues N-terminal of the LX 1 X 2 LF motif,
a second cysteine amino acid residue positioned 15 residues N-terminal of the LX 1 X 2 LF motif,
a third cysteine amino acid residue positioned 9 residues N-terminal of the LX 1 X 2 LF motif,
a fourth cysteine amino acid residue positioned 2 residues N-terminal of the LX 1 X 2 LF motif,
a fifth cysteine amino acid residue positioned 8 residues C-terminal of the LX 1 X 2 LF motif,
a sixth cysteine amino acid residue positioned 12 residues N-terminal of the LX 1 X 2 LF motif; and
two or more disulfide bridges formed between the at least six cysteine amino acid residues; thereby treating the subject.
168 . The method of claim 167 , further comprising delivering the TEAD-binding peptide into a cell of the subject.
169 . The method of claim 167 , comprising binding the TEAD-binding peptide to the TEAD with a K D of less than 40 nM.
170 . The method of claim 167 , further comprising inhibiting yes-associated protein (YAP) binding to a TEAD and tafazzin (TAZ) binding to the TEAD by the binding of the TEAD-binding peptide to the TEAD.
171 . The method of claim 167 , further comprising inhibiting an oncogene in a HIPPO signaling pathway.
172 . The method of claim 167 , wherein the condition with a dysregulated HIPPO pathway is a tumor.
173 . The method of claim 167 , wherein the condition with a dysregulated HIPPO pathway is lung cancer, breast cancer, liver cancer, kidney cancer, colon cancer, stomach cancer, osteosarcoma, brain cancer, leukemia, prostate cancer, or melanoma.