Cell-penetrating compstatin analogs and uses thereof
Inventors
Francois, Cedric • Deschatelets, Pascal • Gerber, Monica
Assignees
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Publication Number
US-11407789-B2
Publication Date
2022-08-09
Expiration Date
Abstract
In some aspects, the present invention cell-penetrating compstatin analog and compositions comprising cell-penetrating compstatin analog. In some aspects, the invention further provides methods of using cell-penetrating compstatin analogs treat a complement-mediated disorder, e.g., to inhibit complement-mediated damage to a cell, tissue, or organ, to inhibit production or release of biologically active C3 cleavage products.
Core Innovation
The invention relates to inhibiting activation of primate complement component 3 (C3) by contacting C3 with a compound comprising a compstatin analog moiety covalently linked to a cell penetrating moiety (CPM). The compstatin analog moiety comprises a peptide comprising an amino acid sequence of one of SEQ ID NOs: 3-6 and 9-36, and the CPM comprises a cell penetrating peptide comprising an amino acid sequence of one of SEQ ID NOs: 77-136.
The disclosure further focuses on compstatin analog construction and connection to the CPM, including cyclic peptide compstatin analogs and defined structural cyclization features. It also describes multivalent and concatemeric formats of compstatin analog constructs, and linking portion L used with the compstatin analog and/or related conjugate architectures.
The cell penetrating moieties are described as poly-N-substituted amino acids/peptoids, including hybrid alpha/beta architectures and related alpha/beta mixed peptoids. The linking arrangements support cleavable or stable linkage concepts and defined conjugate structures.
Claims Coverage
The independent claim covers one core inventive feature: inhibiting primate complement component 3 (C3) activation by contacting C3 with a compound that contains a covalently linked compstatin analog moiety and a cell penetrating moiety (CPM). Dependent claims further narrow the compstatin analog and add structural and linkage constraints.
Covalently linked compstatin analog and cell penetrating moiety for inhibiting primate C3 activation
A method of inhibiting activation of primate complement component 3 (C3) comprising contacting said C3 with a compound comprising a compstatin analog moiety and a cell penetrating moiety (CPM), wherein the compstatin analog moiety includes a peptide comprising an amino acid sequence of one of SEQ ID NOs: 3-6 and 9-36, the CPM includes a cell penetrating peptide comprising an amino acid sequence of one of SEQ ID NOs: 77-136, and wherein the compstatin analog moiety is covalently linked to the CPM.
Cyclic compstatin analog peptide selected from specified SEQ ID NOs
The method further defined such that the compstatin analog is a cyclic peptide with an amino-acid sequence chosen from SEQ ID NOs: 14, 21, 28, 29, 32, 33, 34, or 36.
Linker between compstatin analog moiety and CPM
The method includes linking a compstatin analog moiety to CPM using a linker.
Defined cyclic core sequence with Trp/Trp-analog positions
The compstatin analog moiety is a cyclic peptide whose core sequence is X′aa-Gln-Asp-Xaa-Gly (SEQ ID NO: 3), with X′aa and Xaa selected from Trp and Trp analogs.
Cyclic peptide compstatin analog with blocking moieties and disulfide linkage
The method is characterized by using a compstatin analog moiety that is a cyclic peptide with a specified sequence containing variable amino acid positions, first and optional second blocking moieties, and a disulfide bond linking two cysteine residues.
Positional substituent constraints for a Trp analog
Xaa2 is defined as an analog of tryptophan with specific substituents at the indicated positions.
Overall, the claim coverage centers on covalently linking a compstatin analog peptide from defined SEQ ID NO ranges to a CPM peptide from defined SEQ ID NO ranges. Dependent claims emphasize cyclic peptide sequence selection and additional structural features such as linker use, Trp/Trp-analog positions, blocking moieties, disulfide bonding, and positional substituent patterns for Trp analogs.
Stated Advantages
Enhances inhibition of complement-mediated damage by promoting intracellular entry of C3-binding compstatin analogs through the CPM.
Inhibits activation of primate complement component 3 (C3).
Documented Applications
A method for inhibiting activation of primate complement component 3 (C3) by contacting C3 with a compound comprising a covalently linked compstatin analog moiety and a cell penetrating moiety (CPM).
Intracellular C3 cleavage and downstream components such as C3a, C3b, and iC3b/iC3d.
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