Compositions and methods for treating diseases by inhibiting exosome release
A multipartite peptide that inhibits release of exosomes in a cell, comprising an N-terminal end and a C-terminal end and comprising at least one secretion modifying region (SMR) peptide from HIV-1 Nef and at least one Clusterin (Clu)-binding peptide (Clu-BP). Pharmaceutical compositions comprising these peptides alone or in synergistic combinations with other active agents in methods for treating cancers and/or infectious diseases are further provided herein.
1. A multipartite peptide that inhibits release of exosomes in a cell, comprising an N-terminal end and a C-terminal end and comprising at least one secretion modifying region (SMR) peptide comprising the amino acid sequence VGFPV (SEQ ID NO: 1) or VGFPVAAVGFPV (SEQ ID NO:2) and at least one Clusterin (Clu)-binding peptide (Clu-BP) selected from the group consisting of HPLSKHPYWSQP (SEQ ID NO:3), NTYWSQLLHFQT (SEQ ID NO:4) and SHALPLTWSTAA (SEQ ID NO:5), wherein the multipartite peptide is pegylated.
2. The multipartite peptide of claim 1 , wherein the peptide comprises an SMR peptide at the N-terminal end and an Clu-BP peptide at the C-terminal end.
3. The multipartite peptide of claim 1 , wherein the peptide comprises a Clu-BP peptide at the N-terminal end and an SMR peptide at the C-terminal end.
4. The multipartite peptide of claim 1 , wherein the peptide comprises at least two SMR peptides separated by a spacer peptide, at least two Clu-BP peptides separated by a spacer peptide, or both.
5. A pharmaceutical composition comprising the multipartite peptide of claim 1 and a pharmaceutically acceptable carrier.
6. The pharmaceutical composition of claim 5 , wherein the C-terminal end of the multipartite peptide comprises the Clu-BP peptide.
7. The pharmaceutical composition of claim 5 , wherein the multipartite peptide further comprises an endopeptidase cleavage signal.
8. The pharmaceutical composition of claim 5 , wherein:
the multipartite peptide comprises the amino acid sequence VGFPVAAVGFPV (SEQ ID NO:2);
the N-terminal end of the multipartite peptide is pegylated, and
the C-terminal end of the multipartite peptide comprises the Clu-BP peptide.
9. A method for treating a cancer, comprising:
administering to a subject in need of such treatment an effective amount of the pharmaceutical composition of claim 5 .
10. The method of claim 9 , wherein the subject has breast cancer.
11. The method of claim 9 , further comprising the step of administering to the subject a chemotherapeutic agent.
12. The method of claim 11 , wherein the chemotherapeutic agent is paclitaxel or cisplatin.
13. A method for treating an infectious disease, comprising:
administering to a subject in need of such treatment an effective amount of the pharmaceutical composition of claim 5 .
14. The method of claim 13 , wherein the subject is infected with HIV-1 or HIV-2.