Antiviral drugs targeting the N-terminal domain (NTD) of the coronavirus spike receptor binding domain (RBD)
Inventors
BOHMANN, Jonathan A. • GUTIERREZ, Nadean M. • McDonough, Joseph A. • Campbell, Robert Francis • Joyce, Michael Gordon • Panchal, Rekha • SANKHALA, Rajeshwer • DUPLANTIER, Allen
Assignees
Southwest Research Institute SwRI • Henry M Jackson Foundation for Advancedment of Military Medicine Inc • United States Department of the Army
Publication Number
US-11865111-B2
Publication Date
2024-01-09
Expiration Date
2042-08-11
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Abstract
Antiviral drugs targeting the N-terminal domain (NTD) of the spike receptor binding domain (RBD) and methods of treating a subject suffering from coronavirus.
Core Innovation
The invention is directed to antiviral drugs that specifically target the N-terminal domain (NTD) of the spike receptor binding domain (RBD) of coronavirus spike proteins, including those of SARS-CoV-1, SARS-CoV-2 (Covid-19), and MERS-CoV, along with their variants. These drugs include benzimidazole and piperidine derivatives, as well as certain other small molecules, formulated or administered in pharmaceutically acceptable carriers or salts. The methods disclosed involve administering effective amounts of these compounds to mammalian subjects, including humans, suffering from coronavirus infections.
The problem addressed by the invention stems from the global pandemic caused by coronavirus diseases, particularly COVID-19, and the vital role of the spike glycoprotein—specifically the interactions of its NTD and RBD—in viral entry into host cells. Existing treatments often target viral proteases or other domains, but there is a need for antiviral agents that disrupt spike protein function by targeting these critical domains, thereby inhibiting infection and viral replication.
The compounds were identified through structure-based in-silico screening using a high-resolution model of the spike RBD-NTD-SD1 arrangement, followed by in vitro screening protocols measuring antiviral activity, cytotoxicity, and selectivity against live virus in infected mammalian cells. The invention provides specific chemical entities, including methyl 3-(((3-(5-(1H-benzo[d]imidazol-2-yl)thiophen-3-yl)benzyl)amino)methyl)benzoate, piperidine carboxamide derivatives, dilazep, and N-(2,2,2-trifluoroethyl)-9-(4-(4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamido)piperidin-1-yl)butyl)-9H-fluorene-9-carboxamide as antiviral drugs, and methods of treating subjects infected with SARS-CoV-1, SARS-CoV-2, and MERS-CoV by administration of these compounds.
Claims Coverage
The independent claims cover methods and compounds for antiviral treatment targeting the N-terminal domain of the coronavirus spike protein, particularly benzimidazole and piperidine compounds, as well as specific chemical entities.
Method of treating coronavirus infection with benzimidazole compounds
A method for treatment of SARS-COV-1, SARS-CoV-2 (Covid-19), and MERS-CoV, and their variants, in a mammalian subject in need thereof, comprising administering to the subject an effective amount of benzimidazole compounds selected according to the formulas described, or a pharmaceutically acceptable salt thereof.
Antiviral drug comprising benzimidazole derivative
An antiviral drug for treatment of SARS-COV-1, SARS-CoV-2 (Covid-19), and MERS-CoV, and their variants, in a mammalian subject in need thereof, comprising methyl 3-(((3-(5-(1H-benzo[d]imidazol-2-yl)thiophen-3-yl)benzyl)amino)methyl)benzoate.
Method of treating coronavirus infection with piperidine compounds
A method for treatment of SARS-COV-1, SARS-CoV-2 (Covid-19), and MERS-CoV, and their variants, in a mammalian subject in need thereof, comprising administering to the subject an effective amount of selected piperidine compounds listed as: - 1-(3-ethoxy-4-hydroxybenzyl)-N-(3'-fluoro-[1,1'-biphenyl]-3-yl)piperidine-4-carboxamide; - 1-(3-ethoxy-4-hydroxybenzyl)-N-(3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)piperidine-4-carboxamide; - 1-(3-ethoxy-4-hydroxybenzyl)-N-(3'-methoxy-[1,1'-biphenyl]-3-yl)piperidine-4-carboxamide; - N-(3'-chloro-[1,1'-biphenyl]-3-yl)-1-(3-hydroxy-4-methoxybenzyl)piperidine-4-carboxamide; - N-(3'-chloro-[1,1'-biphenyl]-3-yl)-1-(3-ethoxy-4-hydroxybenzyl)piperidine-4-carboxamide; - N-(4'-chloro-[1,1'-biphenyl]-3-yl)-1-(3-ethoxy-4-hydroxybenzyl)piperidine-4-carboxamide; or a pharmaceutically acceptable salt thereof.
The inventive features focus on therapeutic methods and compositions involving specific benzimidazole and piperidine compounds, as well as particular chemical entities, designed to treat infections by coronaviruses targeting the NTD of the spike RBD.
Stated Advantages
The invention provides antiviral drugs capable of reducing viral load and improving viral infection symptoms and/or clinical status in subjects with SARS-CoV-1, SARS-CoV-2, or MERS-CoV infections.
The targeted mechanism involves the N-terminal domain (NTD) of the spike receptor binding domain (RBD), offering a unique approach to inhibiting coronavirus infection and replication.
The compounds exhibit antiviral activity with quantifiable results for inhibition, cytotoxicity, and selectivity index, resulting in effective candidates for coronavirus therapy.
Documented Applications
Methods for treating subjects, particularly mammals, suffering from SARS-CoV-1, SARS-CoV-2 (Covid-19), and MERS-CoV, and their variants, by administration of the disclosed antiviral compounds.
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