Agents and methods for modulating pathogen activity
Inventors
Jennings, Michael P. • Edwards, Jennifer L. • DAY, Christopher J. • MAK, Johnson
Assignees
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Publication Number
US-12564596-B2
Publication Date
2026-03-03
Expiration Date
Abstract
Ligands of complement receptor 3, including ligands of the I domain of the alpha subunit of this receptor, are useful in methods, compositions and articles/devices for inhibiting the interaction of pathogens to a complement receptor 3-expressing cell and for treating or inhibiting the development of infections caused by such pathogens.
Core Innovation
The invention relates to complement receptor 3 (CR3) polypeptide interaction inhibition by non-carbohydrate small-molecule ligands, with emphasis on the CR3 alpha-subunit I-domain (CR3 I-domain) and CR3 (CD11b I-domain) interaction inhibition. It identifies ligands that bind the CR3 I-domain and inhibit pathogen binding and entry by interacting with the CR3 I-domain.
The invention is directed to inhibiting CR3-mediated interactions between pathogens and CR3-expressing immune and epithelial cells and to treating infections in a subject in which the pathogen interacts with a CR3 polypeptide on a CR3 polypeptide-expressing cell. The document frames the approach around a host-mediated, CR3-dependent mechanism and includes Neisseria species, bacteria, fungi, protozoa, and viruses as interacting with CR3-dependent processes.
The disclosed compounds include phenylpropionic acid derivative compounds of Formula (III), with examples including methyldopa and related derivatives, together with other CR3 I-domain ligand scaffolds including dibenzoazepines (Formula I) and anthranilic acid fenamates (Formula II). The document describes binding of carbamazepine, methyldopa, and flufenamic acid to the CR3 I-domain and competitive blockade of Neisseria pilin and HIV interactions, together with inhibition of CR3-dependent adherence and host-mediated killing in cervical epithelial and CHO-CR3 models.
Claims Coverage
The document includes two independent method claims that share the same central inventive concept: administering an effective amount of a phenylpropionic acid derivative compound of Formula (III) to target a pathogen process involving CR3 polypeptide interaction, without co-administering another antimicrobial agent. Across the independent claims, the scope is organized into treatment of an infected subject and reduction of likelihood of infection or recurrence in a susceptible subject.
Treatment of Neisseria infection via CR3 polypeptide interaction inhibition without co-administered antimicrobial
A method of treating an infection with a pathogen in a subject infected with the pathogen, wherein the pathogen is a Neisseria species that interacts with a complement receptor 3 (CR3) polypeptide of a CR3 polypeptide-expressing cell, the method comprising administering to the subject an effective amount of a phenylpropionic acid derivative compound of Formula (III), without administering another antimicrobial agent.
Reducing likelihood of Neisseria infection or recurrence via CR3 polypeptide interaction inhibition without co-administered antimicrobial
A method of reducing likelihood of developing an infection with a pathogen in a subject not infected with the pathogen but known to be susceptible, or in a subject considered likely to develop a recurrence of a previously treated infection, wherein the pathogen is a Neisseria species that interacts with a complement receptor 3 (CR3) polypeptide of a CR3 polypeptide-expressing cell, the method comprising administering to the subject an effective amount of a phenylpropionic acid derivative compound of Formula (III), without administering another antimicrobial agent.
Across both independent claims, the central coverage is directed to administering an effective amount of a phenylpropionic acid derivative compound of Formula (III) for Neisseria species that interact with CR3 polypeptide-expressing cells, with the requirement that the compound is administered without administering another antimicrobial agent.
Stated Advantages
Inhibits pathogen binding and entry mediated by the CR3 I-domain.
Treats infections caused by pathogens, including Neisseria species, that interact with CR3 polypeptide-expressing cells.
Reduces the likelihood of developing an infection in susceptible subjects and reduces the likelihood of recurrence of a previously treated infection.
Competitively blocks pathogen interactions involving Neisseria pilin and HIV interactions with CR3 I-domain.
Reduces CR3-dependent adherence and host-mediated killing in cervical epithelial and CHO-CR3 models.
Documented Applications
Treating a subject infection with a pathogen wherein the pathogen is a Neisseria species that interacts with a CR3 polypeptide of a CR3 polypeptide-expressing cell.
Reducing the likelihood of developing an infection with a Neisseria species in susceptible subjects or reducing the likelihood of recurrence of a previously treated infection.
Use of topical formulations and intrauterine delivery contexts, including intrauterine contraceptive devices, for I-domain ligands to block interactions of pathogens with CR3-expressing immune and epithelial cells [procedural detail omitted for safety].
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