Compositions for preventing or treating coronavirus infections
Inventors
Liu, Cheng • Zhang, Hongbing • CUI, Ziyou • Yang, Zhiyuan • Chen, Jinyun • Liu, Jingbao • Xiong, Guangyan • Greene, Warner
Assignees
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Publication Number
US-12460193-B2
Publication Date
2025-11-04
Expiration Date
Abstract
The present application relates to compositions for preventing or treating infections. In some embodiments, the present application provides chimeric proteins comprising a target-binding moiety comprising an extracellular binding domain (EBD) of an angiotensin-converting enzyme 2 (ACE2) protein or a fragment thereof that specifically binds to an S protein, and a positively charged mucoadhesive peptide fragment. Compositions comprising the chimeric proteins described herein are useful for preventing or treating a viral infection in an individual, such as a coronavirus infection.
Core Innovation
The invention relates to a chimeric protein comprising an ACE2 target-binding moiety and a mucoadhesive peptide fragment. The target-binding moiety comprises an extracellular binding domain (EBD) of an angiotensin-converting enzyme 2 (ACE2) protein, or a fragment or variant thereof, that specifically binds to a spike (S) protein. The mucoadhesive peptide fragment comprises at least 5 positively charged amino acid residues and facilitates attachment of the chimeric protein to a mucosa.
The mucoadhesive peptide fragment does not comprise six consecutive histidines. The described mucoadhesive peptide fragments include contiguous positively charged residue regions, including polyarginine peptide fragments with contiguous arginines and polyornithine peptide fragments with contiguous ornithines, optionally with non-positively charged polar or nonpolar residues. The invention further specifies charge-percentage thresholds, mucoadhesive peptide molecular weight limits, and maintenance of folding/secretion and binding to spike S1.
The invention also describes chimeric proteins that incorporate the ACE2-derived spike-binding domain together with mucoadhesive peptides and additional domains via linkers. The constructs may include flexible or cleavable peptide linkers, multimerization/oligomerization domains, and Fc/antibody constant regions. The disclosure further states coronavirus prevention and/or treatment via mucosal administration, including a nasal spray, and antiviral activity supported by complement system activation, including C1/C4/MAC and complement-mediated in vitro killing/neutralization.
Claims Coverage
The independent claim coverage is directed to chimeric proteins combining an ACE2-derived spike-binding extracellular binding domain with a mucoadhesive peptide fragment that promotes mucosal attachment. The inventive features are centered on ACE2 EBD spike specificity, mucoadhesion via a positively charged peptide fragment with explicit exclusion of six consecutive histidines, and functional outcomes including mucosal attachment and complement-supported antiviral activity in dependent claim contexts.
Ace2 ebd-based spike binding with mucoadhesion
A chimeric protein comprising a target-binding moiety including an extracellular binding domain (EBD) of an ACE2 protein (or a fragment or variant) that specifically binds a spike(S) protein, and a mucoadhesive peptide fragment comprising at least 5 positively charged amino acid residues that does not comprise six consecutive histidines, wherein the mucoadhesive peptide fragment facilitates attachment to a mucosa.
Contiguous positively charged residues and biophysical constraints
A chimeric protein in which the mucoadhesive peptide fragment contains at least five contiguous positively charged amino acid residues, interspersed with non-positively charged residues, and is no more than about 15 kD and/or has an isoelectric point (pI) higher than the pH of the mucosa.
Defined ace2-derived binding domain sequence ranges or seq id no s
A chimeric protein in which the target-binding moiety comprises particular hACE2-derived amino-acid regions (or 90% sequence-identity variants) and/or specific sequences identified as SEQ ID NOs 102 and 8 and/or one of SEQ ID NOs 1-7, 9-14, and 135 (or 90% sequence-identity variants).
Animal ace2 ebd retaining spike specificity
A chimeric protein whose target-binding moiety is the EBD from an animal ACE2 protein (or a fragment or variant) that specifically binds to a spike (S) protein.
Coronavirus s protein specificity
A chimeric protein with a coronavirus S protein, where the coronavirus is selected from SARS-COV, SARS-COV-2, and HCoV-NL63.
Complement-mediated in vitro virus killing or neutralization
An in vitro method that kills or neutralizes a virus by contacting it with the chimeric protein and at least one component of the complement system, wherein the chimeric protein specifically binds the virus spike (S) protein.
Across the independent-claim family coverage provided, the main inventive concept is a chimeric protein that combines an ACE2 EBD-derived spike-binding moiety with a mucoadhesive positively charged peptide fragment (excluding six consecutive histidines) to enable mucosal attachment, with dependent refinements specifying contiguous charge arrangement and biophysical constraints, defined ACE2-derived binding domain sequence ranges/SEQ ID NOs, selection among named coronavirus spike targets, and complement-supported in vitro killing/neutralization.
Stated Advantages
Facilitates attachment of the chimeric protein to a mucosa.
Increases mucin binding and retention.
Enables complement-supported antiviral activity including in vitro killing/neutralization via contacting with components of the complement system.
Pseudovirus infection blocking for SARS-CoV-2 variants.
Complement activation and virus killing/neutralization.
Documented Applications
Coronavirus prevention and/or treatment via mucosal administration, including administration as a nasal spray.
In vitro method for killing or neutralizing a virus by contacting the virus with the chimeric protein together with a component of the complement system.
Activation of the complement pathway (C1/C4/MAC) to support antiviral activity.
Protection in hACE2 transgenic mice against Delta/Omicron pseudoviruses.
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