Proline-rich peptides protective against S. pneumoniae
Inventors
Ghasparian, Arin • Zuniga, Armando • Geib, Nina • Tamborini, Marco • Jud, Maja • Pluschke, Gerd • Marrero Nodarse, Aniebrys • Robinson, John Anthony
Assignees
VIROMETIX AG • Universitaet Basel • Zurich Universitaet Institut fuer Medizinische Virologie • Schweizerisches Tropen und Public Health Institut
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Publication Number
US-9943583-B2
Publication Date
2018-04-17
Expiration Date
Abstract
The invention relates to lipopeptides consisting of a peptide chain comprising a parallel coiled-coil domain, a proline-rich peptide antigen, and a lipid moiety, all covalently linked, which aggregate to synthetic virus-like particles. Proline-rich peptide antigens considered contain negatively and positively charged amino acid, and at least 15% of the amino acids are proline. Such synthetic virus-like particles carrying proline-rich antigens derived from pneumococcal proteins are useful as vaccines against infectious diseases caused by Gram-positive bacteria such as Streptococcus pneumoniae.
Core Innovation
The invention provides a lipopeptide building block in which a peptide chain, a proline-rich peptide antigen, and a lipid moiety are covalently linked, either directly or through a linker. The peptide chain comprises a parallel coiled-coil domain that, as a self-standing lipid-free peptide, forms a parallel dimeric, trimeric or higher order oligomeric helical bundle.
The proline-rich peptide antigen comprises at least one negatively and at least one positively charged amino acid, at least 15% proline, and consists of 8-80 amino acids. It comprises any one of sequences selected from SEQ ID NO:27 to 112, or such a sequence in which one, two or three amino acids are replaced by other amino acids.
The lipid moiety comprises two or three long hydrocarbyl chains. The disclosure also describes artificial proline-rich antigen sequences constructed by fusion of PR segments from PspA proteins, combined with maleimide conjugation handles, and maleimidopeptide-lipopeptide conjugates are formed and characterized.
Claims Coverage
The independent claim defines one central construct with three covalently linked components: a parallel coiled-coil helical bundle peptide chain, a charged proline-rich peptide antigen with specified SEQ ID coverage, and a lipid moiety with two or three long hydrocarbyl chains. Dependent claims further specify the lipid moiety identity, coiled-coil architecture, and synthetic virus-like particles.
Parallel coiled-coil domain forming an oligomeric helical bundle
A peptide chain comprising a parallel coiled-coil domain which, as a self-standing lipid-free peptide, forms a parallel dimeric, trimeric or higher order oligomeric helical bundle.
Proline-rich peptide antigen with charged residues, proline content, and SEQ ID sequence selection
A proline-rich peptide antigen comprising at least one negatively and at least one positively charged amino acid, wherein at least 15% of the amino acids are proline, consisting of 8-80 amino acids, and comprising any one of sequences selected from SEQ ID NO:27 to 112 or such a sequence wherein one, two or three amino acids are replaced by other amino acids.
Lipid moiety with two or three long hydrocarbyl chains covalently linked to the peptide and antigen
A lipid moiety comprising two or three long hydrocarbyl chains, wherein the peptide chain, the proline-rich peptide antigen and the lipid moiety are covalently linked, either directly or through a linker.
Lipid moiety as di-palmitoyl-S-glycerylcysteinyl of formula Z3
The lipid moiety is di-palmitoyl-S-glycerylcysteinyl of formula Z3.
Coiled-coil domain comprising three to eight heptad motifs
The peptide chain includes a coiled-coil domain made up of three to eight heptad motifs.
Heptad motif residue constraints at positions a and d with substitution possibilities
The coiled-coil domain positions a and d in each heptad motif (abcdefg) comprise alpha-amino acids with defined side-chain properties, allowing specific substitutions with polar residues, their acylated derivatives, or glycine in zero to two of the a/d positions.
Synthetic virus-like particles from helical lipopeptide bundles of defined building block number
Synthetic virus-like particles are formed from helical lipopeptide bundles containing two to seven lipopeptide building blocks as defined in claim 1.
Overall, the claim coverage centers on covalently linking a parallel coiled-coil helical bundle-forming peptide chain, a highly proline-rich charged proline-rich peptide antigen selected from SEQ ID NO:27-112 with optional one to three substitutions, and a lipid moiety bearing two or three long hydrocarbon chains.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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