Lipid-peptide-polymer conjugates and nanoparticles thereof
The present invention provides a conjugate having a peptide with from about 10 to about 100 amino acids, wherein the peptide adopts a helical structure. The conjugate also includes a first polymer covalently linked to the peptide, and a hydrophobic moiety covalently linked to the N-terminus of the peptide, wherein the hydrophobic moiety comprises a second polymer or a lipid moiety. The present invention also provides helix bundles form by self-assembling the conjugates, and particles formed by self-assembling the helix bundles. Methods of preparing the helix bundles and particles are also provided.
1. A conjugate comprising:
a helix bundle-forming helical peptide selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 5;
a first polymer covalently linked to the helical peptide, wherein the first polymer is linked to the helical peptide at an amino acid other than the N- or C-terminus; and
a hydrophobic moiety covalently linked to the N-terminus of the helical peptide, wherein the hydrophobic moiety comprises a second polymer or a lipid moiety comprising from 1 to 6 C 10-20 alkyl groups.
2. The conjugate of claim 1 , wherein the first polymer is a hydrophilic polymer.
3. The conjugate of claim 1 , wherein the first polymer is polyethyleneglycol.
4. The conjugate of claim 1 , wherein the second polymer comprises polybutadiene.
5. The conjugate of claim 1 , wherein the lipid moiety comprises 1, 2 or 4 C 10-20 alkyl groups.
6. The conjugate of claim 1 , further comprising an amino acid residue covalently linked to the C-terminus of the helix bundle-forming helical peptide.
7. The conjugate of claim 6 , wherein the amino acid residue comprises a member selected from the group consisting of GGG, HHH, KK, EE, RGD, and AYSSGAPPMPPF (SEQ ID NO: 3).
8. The conjugate of claim 1 , wherein
the helix bundle-forming helical peptide comprises SEQ ID NO: 1;
the first polymer comprises polyethylene glycol;
the hydrophobic moiety comprises the lipid moiety which comprises lysine and two C 16 alkyl chains; and
an amino acid residue of from 2 to about 20 amino acids, covalently linked to the C-terminus of the peptide.
9. A helix bundle comprising from 2 to 6 conjugates of claim 1 .
10. The helix bundle of claim 9 , comprising 3 conjugates.
11. The helix bundle of claim 9 , comprising 4 conjugates.
12. A particle comprising from about 20 to about 200 conjugates of claim 1 .
13. The particle of claim 12 , further comprising at least one member selected from the group consisting of a therapeutic agent, a diagnostic agent, DNA, and an oligonucleotide.
14. A method of forming a particle of claim 12 , the method comprising:
contacting a plurality of conjugates of claim 1 such that the conjugates self-assemble to form the particles of claim 12 .
15. The method of claim 14 , wherein the conjugates are at a concentration of from about 1 nM to about 1 M.