Targeting papain-like protease for broad-spectrum coronaviruses inhibition
Inventors
YUAN, Shuofeng • CHAN, Fuk Woo Jasper • Yuen, Kwok Yung
Assignees
Versitech Ltd • Centre for Virology Vaccinology and Therapeutics Ltd
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Publication Number
US-11986478-B2
Publication Date
2024-05-21
Expiration Date
Abstract
The subject invention pertains to compounds and methods of using said compounds to target the multi-functional papain-like protease (PLpro) domain of the viral Nsp3, specifically F0213, F0326, and F0393 that can have broad anti-coronavirus activity, including SARS-CoV-2, MERS-CoV, and coronaviruses hCoV-229E and hCoV-OC43. F0213, F0326, and F0393 can possess a dual therapeutic functionality that suppress CoV replication via blocking viral polyprotein cleavage, as well as promote antiviral immunity by antagonizing the PLpro deubiquitinase activity.
Core Innovation
The invention relates to pan-coronavirus inhibition by targeting the viral papain-like protease (PLpro) on viral Nsp3. Noncovalent PLpro inhibitors are disclosed as F0213 (formula (I)), F0326 (formula (II)), and F0393 (formula (III)), and are described as blocking viral polyprotein cleavage to suppress replication across coronavirus types including SARS-CoV-2, SARS-CoV, MERS-CoV, and human coronaviruses 229E and OC43.
The inhibitors are also described as antagonizing PLpro deubiquitinase activity and PLpro deISGylation activity. The disclosed mechanism includes inhibiting cleavage of ISG15 from substrates and inhibiting cleavage of ubiquitin chains, including ISG15 and ubiquitin substrates, and this dual functionality is presented as promoting antiviral innate immunity by antagonizing PLpro deubiquitinase/deISGylation activities.
The patent further describes biological characterization showing cross-viral activity and variant coverage, supported by high-throughput screening and in vitro antiviral potency across SARS-CoV-2 variants of concern. It also describes reporter assays for IFN-β/NF-κB/IRF3 and ISG15/PKR modulation, specificity evaluations against host DUBs/proteases, docking and site mutagenesis, and in vivo efficacy in hamster and hDPP4-KI mouse models.
Claims Coverage
The partial content includes two independent claims. Claim coverage is based on two inventive areas: a prophylactic or responsive treatment method using specific PLpro inhibitors, and a composition of matter comprising combinations of those inhibitors.
Prophylactic or responsive treatment using F0213, F0326, and F0393 PLpro inhibitors
A method for prophylactic or responsive treatment of a human coronavirus infection or a symptom thereof in a human subject by administering an effective amount of a papain-like protease (PLpro) inhibitor, where the PLpro inhibitor is F0213 (formula (I)), F0326 (formula (II)), and/or F0393 (formula (III), or a pharmaceutically acceptable salt, derivative, or prodrug of any thereof.
Combination composition of at least two PLpro inhibitors selected from F0213, F0326, and F0393
A composition of matter comprising a combination of at least two compounds selected from F0213 (formula (I)), F0326 (formula (II)), and/or F0393 (formula (III), or a pharmaceutically acceptable salt, derivative, or prodrug of any thereof.
Across the independent claims, the coverage centers on administering F0213, F0326, and/or F0393 as PLpro inhibitors for prophylactic or responsive treatment of human coronavirus infection or symptoms, and on combinations of at least two of these compounds as a composition of matter, including pharmaceutically acceptable salts, derivatives, or prodrugs.
Stated Advantages
Broad anti-coronavirus coverage against SARS-CoV-2, SARS-CoV, and MERS-CoV, and activity against human coronaviruses 229E and OC43.
Dual functionality by blocking viral polyprotein cleavage to suppress replication and antagonizing PLpro deubiquitinase/deISGylation activities to promote antiviral innate immunity.
Demonstrated in vitro antiviral potency across SARS-CoV-2 variants of concern.
Cross-viral activity against multiple human-pathogenic coronaviruses.
Reported specificity against host DUBs/proteases.
Reported in vivo efficacy including hamster lung viral reduction/pathology and hDPP4-KI mouse survival and viral load reduction.
Documented Applications
Prophylactic or responsive treatment of a human coronavirus infection or a symptom thereof in a human subject.
Use in treating specific coronaviruses including SARS-CoV-2, SARS-CoV, MERS-CoV, and common human coronaviruses selected from 229E, NL63, OC43, and HKU1.
Subject identification prior to administering treatment by assaying a biological sample for coronavirus nucleic acid or coronavirus protein.
Therapeutic and prophylactic use as described in the method claim, including infected-at-administration and previously infected subjects.
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