Covalent inhibitors of coronavirus papain-like protease
Inventors
Sanders, Brian • Galanie, Stephanie S. • Parks, Jerry M.
Assignees
Publication Number
US-12234202-B2
Publication Date
2025-02-25
Expiration Date
2042-08-26
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Abstract
A compound having the following structure: wherein: R1 is a linker having the formula —(CH2)n-L1-, wherein L1 contains 1-6 carbon atoms and at least one —NH— linkage and at least one oxygen-containing or sulfur-containing linkage, and n is an integer of 0-3; R2 is a group having the formula —C(Y)-E, wherein Y is O or S, and E is a hydrocarbon group and either: (i) at least one carbon-carbon or carbon-nitrogen unsaturated bond or (ii) at least one alkyl halide group; R3 is selected from H, NR′2, NHC(O)R′, and —(CH2)p-T, wherein T contains at least one —NH— linkage; Ra, Rb, Rc, Rd, Re, and Rf are independently selected from of H, hydrocarbon groups containing 1-3 carbon atoms, fluorine atom, and chlorine atom; X is N or CR9, wherein R9 is selected from H, hydrocarbon groups containing 1-3 carbon atoms, fluorine atom, and chlorine atom; and pharmaceutically acceptable salts thereof.
Core Innovation
The invention relates to covalent inhibitor molecules of coronavirus papain-like protease (PLpro), specifically substituted (R)—N-(1-(naphthalen-1-yl)ethyl)benzamide compounds with particular structural characteristics. These compounds contain a carefully designed peptidomimetic linker (R1) with at least one —NH— linkage and at least one oxygen- or sulfur-containing linkage, an electrophilic warhead (R2) capable of covalent bond formation with the PLpro active site, and specific substituents in the benzamide region (R3) that enhance binding and efficacy. The inhibitor design features aim to mimic essential substrate interactions and enable potent, selective, covalent inhibition of the PLpro enzyme.
The problem addressed by this invention is the urgent need for new direct-acting antiviral therapeutics targeting SARS-CoV-2 and other coronaviruses. Existing drugs for COVID-19 are limited in efficacy and scope, and vaccines are constrained by variant strains, limited availability, and breakthrough infections. Notably, previous drug repurposing efforts have generally failed, highlighting the need to develop pharmaceutical treatments that directly target essential coronavirus enzymes such as PLpro, which plays key roles in viral replication and interference with host immune responses.
This invention provides a solution by designing and synthesizing a new class of covalent PLpro inhibitors that fit into the narrow substrate binding cleft of the enzyme, form stable covalent bonds with the catalytic cysteine (Cys111), and mimic important interactions of the virus’s native substrates. The molecules include variations with hydrazide-containing linkers and diverse electrophilic warheads, showing nanomolar potency in inhibition assays and the potential for use in pharmaceutical compositions or combination therapy for treating coronavirus infections.
Claims Coverage
The patent contains multiple independent claims focused on novel compounds, pharmaceutical compositions, and treatment methods. There are three principal inventive features described in the independent claims.
Covalent PLpro inhibitor with specific substituent structure
A compound having a core (R)—N-(1-(naphthalen-1-yl)ethyl)benzamide structure with: - R1: a linker of formula —(CH2)n-L1-, where L1 contains 1–6 carbon atoms, at least one —NH— linkage, and at least one oxygen- or sulfur-containing linkage; n = 0–3 - R2: a group of formula —C(Y)-E, where Y is O or S, and E is a hydrocarbon (1–12 carbons) with (i) at least one carbon-carbon or carbon-nitrogen unsaturated bond or (ii) at least one alkyl halide group - R3: selected from H, NR'2, NHC(O)R', or —(CH2)p-T, with T containing at least one —NH— linkage - Ra–Rf: independently H, 1–3 carbon hydrocarbon, F, or Cl - X: N or CR9, with R9 as H, C1–C3 hydrocarbon, F, or Cl - Pharmaceutically acceptable salts thereof
Pharmaceutical composition comprising the compound
A pharmaceutical composition that includes: - At least one compound of Formula (1) as described directly in the claims - A pharmaceutically acceptable carrier, excipient, or vehicle for effective delivery
Method of inhibiting PLpro activity or treating coronavirus infection
A method for inhibiting papain-like protease (PLpro) activity in a subject and/or treating coronavirus infection, comprising: - Administering a therapeutically effective dosage of a compound of Formula (1) to the subject - Achieving inhibition of PLpro activity and/or prevention or treatment of coronavirus symptoms - Specification that the PLpro activity is mediated by coronavirus PLpro
These inventive features collectively protect the novel PLpro-inhibiting compound structure, its use in pharmaceutical compositions, and therapeutic methods for inhibiting coronavirus PLpro and treating coronavirus infections.
Stated Advantages
Provides potent covalent inhibition of coronavirus PLpro, achieving nanomolar inhibitory activity and confirmed covalent bond formation with the catalytic cysteine.
Demonstrates selectivity over human deubiquitinases, reducing the risk of off-target activity.
Shows antiviral efficacy in vitro against SARS-CoV-2, including activity against different viral variants and in various cell lines.
The design enables fit into the narrow substrate binding groove of PLpro and mimics critical Gly-Gly linkages of native substrates for enhanced specificity.
Potential for use as a screening tool in the identification and characterization of resistant PLpro mutants or to determine binding sites of other antivirals.
Documented Applications
Inhibition of papain-like protease (PLpro) activity, including that mediated by coronavirus PLpro, in a subject.
Treatment of coronavirus infection in a subject, resulting in inhibition or prevention of coronavirus symptoms.
Use in pharmaceutical compositions for therapeutic administration against coronavirus-related diseases such as COVID-19.
Use as a tool compound in screening assays to discover additional antiviral agents, identify resistant PLpro mutants, or determine binding sites for PLpro inhibitors.
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