Peptidic nanoparticles as drug delivery and antigen display systems
Described is a new type of nanoparticle using the concept of self-organization of a single continuous chain to form peptidic nanoparticles. In particular, nanoparticles of the invention consist of aggregates of a continuous chain comprising two peptidic oligomerization domains connected by a linker segment. Preferred are coiled-coil oligomerization domains with a contiguous pattern of hydrophobic residues spaced 3 and 4 residues apart. The invention provides a drug targeting and delivery system comprising a functionalized peptidic nanoparticle comprising ligands capable of binding a receptor and drugs, and a method of treating or diagnosing humans using such functionalized peptidic nanoparticles. The invention further provides an antigen display system to be used as efficient vaccines comprising a functionalized peptidic nanoparticle comprising an antigen, and a method of vaccinating humans or non-human animals using such functionalized peptidic nanoparticles. The invention also provides processes for making peptidic nanoparticles and functionalized peptidic nanoparticles, and monomeric building blocks suitable for forming such nanoparticles.
1. A peptidic nanoparticle consisting of an assembly of 10 or more peptides, in which each peptide is consisting of a continuous chain of a peptidic oligomerization domain D1, a linker segment L, and a peptidic oligomerization domain D2 of formula (I):
D1-L-D2 (I),
wherein
each D1 is a synthetic or natural peptide, and a plurality of D1 form at least one protein oligomer assembly (D1) m , wherein the protein oligomer assembly consists of m subunits of D1,
each D2 is a synthetic or natural peptide, and a plurality of D2 form at least one protein oligomer assembly (D2) n , wherein the protein oligomer assembly consists of n subunits of D2,
the peptidic nanoparticle contains:
(a) one of m or n is 2 forming a dimer protein oligomer assembly, and the other of m or n is 5 forming a pentamer protein oligomer assembly; or
(b) one of m or n is 3 forming a trimer protein oligomer assembly, and the other of m or n is 4 or 5 forming a tetramer or pentamer protein oligomer assembly, respectively; or
(c) one of m or n is 4 forming a tetramer protein oligomer assembly, and the other of m or n is 5 forming a pentamer protein oligomer assembly;
L is a short flexible linker segment,
at least one D1 or D2 is a coiled-coil peptide sequence, and
D1, D2 or L is optionally further substituted by a substituent selected from a targeting entity, drug and antigen.
2. A peptidic nanoparticle according to claim 1 wherein m or n is 5.
3. A peptidic nanoparticle according to claim 1 wherein at least one peptide is different from a viral capsid protein.
4. A peptidic nanoparticle according to claim 1 wherein at least one D1 and D2 are coiled-coil peptide sequences.
5. A peptidic nanoparticle according to claim 1 wherein at least one peptide is linked to a targeting entity.
6. A peptidic nanoparticle according to claim 1 wherein at least one peptide is linked to a drug.
7. A peptidic nanoparticle according to claim 1 wherein at least one peptide is linked to an antigen.
8. A peptidic nanoparticle according to claim 1 wherein at least one peptide is non-covalently linked to a targeting entity, drug or antigen.
9. A pharmaceutical composition comprising a peptidic nanoparticle according to claim 1 .
10. A peptidic nanoparticle according to claim 1 wherein m or n is 4.
11. A method for determining whether a human has diseased organs or tissues comprising:
administering an effective amount of a functionalized peptidic nanoparticle according to claim 1 which is substituted with a drug that is a diagnostic molecule.