SARS-CoV-2 epitope-targeted peptide immunostimulants
Inventors
Heath, James R. • Idso, Matthew • Winton, Alexander J. • Coppock, Matthew B. • Liu, Sanchao
Assignees
Institute for Systems Biology • United States Department of the Army
Publication Number
US-12209142-B2
Publication Date
2025-01-28
Expiration Date
2041-06-01
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Abstract
Disclosed are compounds, compositions, and methods relating to epitope-targeted immunostimulants (EPIs), which comprise a synthetic peptide ligand and an antibody-recruiting moiety. The peptide ligand binds an epitope on a target and the antibody-recruiting moiety recruits antibodies to the target when the EPI is bound to the epitope on the target. Also disclosed are compositions comprising any of the disclosed EPIs. Also disclosed are methods of stimulating an immune reaction to a microorganism or other pathogen in a subject where an EPI is administered to the subject. Also disclosed are methods of identifying the peptide ligand by using multi-omic analysis.
Core Innovation
Disclosed are compounds, compositions, and methods relating to epitope-targeted immunostimulants (EPIs), which comprise a synthetic peptide ligand and an antibody-recruiting moiety. The peptide ligand binds an epitope on a target, and the antibody-recruiting moiety recruits antibodies to the target when the EPI is bound to the epitope. EPIs can be used to stimulate immune reactions by administering an EPI that targets a microorganism or other pathogen in a subject.
The problem being solved is the urgent need for effective therapies against pathogens, particularly antibiotic-resistant bacteria such as carbapenem-resistant Klebsiella pneumoniae, and emerging pathogens like SARS-CoV-2. The rapid spread and high mortality of SARS-CoV-2 and the increasing incidence of antibiotic-resistant bacterial infections expose gaps in current treatment options. There is also a challenge in rapidly developing targeted antibiotics and immunostimulants that are effective against such pathogens.
The disclosed innovation proposes creating EPIs that combine a synthetic peptide ligand targeting specific epitopes on pathogen surface molecules with an antibody-recruiting moiety to enhance immune clearance. The peptide ligands can be identified via non-catalyzed in situ click chemistry screening of combinatorial peptide libraries against selected epitopes that are highly exposed and have low homology with the human proteome. EPIs can be cycled or linear peptides comprising specific residues, such as 1,4- or 1,5-substituted-1,2,3-triazole residues. The antibody-recruiting moiety can be an epitope such as 2,4-dinitrophenyl (DNP) that recruits endogenous antibodies, mediating recognition and phagocytosis by immune cells.
Claims Coverage
The patent contains one independent claim directed to an epitope-targeted immunostimulant (EPI) comprising defined synthetic peptide ligands linked to an antibody-recruiting moiety targeted to the SARS-CoV-2 spike protein.
Epitope-targeted immunostimulant structure
An EPI comprising a synthetic peptide ligand conjugated or coupled to an antibody-recruiting moiety, wherein the peptide ligand has affinity for an epitope on a SARS-CoV-2 protein exposed on a surface of the target, and the antibody-recruiting moiety recruits antibodies to the target when bound.
Synthetic peptide ligand specificity
The synthetic peptide ligand comprises one or more amino acid sequences selected from a long list of specific sequences (SEQ ID NOs: 80-215), targeting epitopes on the SARS-CoV-2 spike protein.
Peptide ligand structural features
The peptide ligand can be cyclic and may comprise a 1,4-substituted or 1,5-substituted 1,2,3-triazole residue.
Method of identifying peptide ligands
The peptide ligand was identified by non-catalyzed in situ click chemistry screening of a combinatorial peptide library against selected epitopes of the SARS-CoV-2 spike protein.
Target epitopes on SARS-CoV-2 spike protein
The target epitopes include amino acid sequences YGFQPTNGVGYQ, CNGVEGENCYGPLQS, SPDVDLGDISGINA, SCVIRGDEVRQCAPG, YGVSPTKLNDLCFTNV, TNLCPFGEVENAT, TESNKKFLPFQQFGRDIA, or GQTGKIADYNYKL.
Antibody-recruiting moiety function
The antibody-recruiting moiety comprises an epitope recognized by antibodies that mediate recognition and phagocytosis by immune cells; such epitopes are immunogens endogenously recognized by the mammalian or human immune system, examples include 2,4-dinitrophenyl (DNP), alpha-galactose, beta-lactam, avidin, fluorescein, and others.
Multi-ligand simultaneous binding
The peptide ligand can be part of a multi-ligand construct covalently linked to a second ligand that binds a different epitope on the target molecule, enabling simultaneous binding to both epitopes on the SARS-CoV-2 protein.
Pharmaceutical composition including EPI
Compositions comprising the disclosed EPI and a pharmaceutically acceptable carrier.
Method to stimulate immune reaction
A method for stimulating an immune reaction to SARS-CoV-2 in a subject by administering the EPI composition targeting the virus.
The claims cover an epitope-targeted immunostimulant designed to target specific epitopes on the SARS-CoV-2 spike protein via synthetic peptide ligands identified by click chemistry screening, conjugated to antibody-recruiting moieties that enhance immune recognition and clearance. The invention also contemplates multi-ligand constructs, pharmaceutical compositions, and methods of stimulating immune response against SARS-CoV-2.
Stated Advantages
EPIs can be rapidly developed against virtually any epitope on a bacterial or viral surface, enabling swift countermeasures to emerging pathogens.
EPIs display relatively low cost and high thermal stability, facilitating scalability and transport without significant loss of efficacy.
EPIs exhibit high specificity for targeted epitopes, reducing off-target effects compared to other synthetic immunostimulants.
The all-synthetic nature of EPIs allows accelerated design, construction, and deployment, capable of addressing rapid pandemic outbreaks such as SARS-CoV-2.
Chemical modifications of EPIs enable optimization of pharmacokinetic properties and binding avidity.
Documented Applications
Stimulating immune reactions to pathogens, including SARS-CoV-2 virus, carbapenem-resistant Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), and other antibiotic-resistant bacteria.
Use as targeted antibiotics or immunostimulatory agents for the treatment of infections caused by multidrug-resistant bacteria and viruses.
Development of cocktails of EPIs targeting multiple conserved surface epitopes on a single pathogen to enhance clearance of heterogeneous bacterial populations.
Methods of administering EPI compositions to subjects to promote opsonization, phagocytosis, and opsonophagocytic killing by immune cells.
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