Antiviral agents and uses thereof
Inventors
Von Itzstein, Mark • El-Deeb, Ibrahim • Dirr, Larissa • Guillon, Patrice • Winger, Moritz
Assignees
Publication Number
US-10028938-B2
Publication Date
2018-07-24
Expiration Date
2035-09-07
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Abstract
The present invention relates to compounds which are found to exhibit an antiviral effect. The compounds are modulators of the activity of the viral haemagglutinin and/or neuraminidase enzymes.
Core Innovation
The invention relates to novel compounds that exhibit antiviral effects by modulating the activity of viral haemagglutinin and/or neuraminidase enzymes. Specifically, the compounds are designed to inhibit these enzymes, which play crucial roles in the infection process of viruses such as human parainfluenza viruses (hPIV) types 1 to 3 and influenza virus types A, B, and C. The compounds have a defined chemical structure featuring variations at specified positions to enhance antiviral potency.
The problem addressed by the invention stems from the significant health burden caused by viruses of the Orthomyxoviridae and Paramyxoviridae families, including hPIV responsible for serious respiratory diseases in infants, young children, the elderly, and immunocompromised individuals. Current lack of vaccines or specific antiviral therapies for hPIV infections highlights the need for effective antiviral agents. The invention aims to provide compounds that can inhibit the multifunctional haemagglutinin-neuraminidase surface glycoprotein of parainfluenza viruses, thereby preventing virus attachment, fusion activation, and release.
Compounds of the invention, such as those represented by formulae (I), (II), (III), and (IIIa), include novel neuraminic acid derivatives with specific substitutions designed to engage the viral haemagglutinin-neuraminidase enzyme binding sites. Molecular modelling guided the design of compounds with bulky C4 substituents and optimized C5 acylamino moieties which lock open the viral 216 loop, a dynamic region critical for enzyme activity. Biological and structural studies demonstrated that these inhibitors possess enhanced potency relative to prior art compounds, effectively inhibiting neuraminidase and haemagglutinin activities and reducing viral replication in cell assays.
Claims Coverage
The patent discloses seven independent claims focusing on novel antiviral compounds, pharmaceutical compositions, methods of treatment, and enzyme modulation approaches.
Compounds of formula (I) with specific substitutions
Compounds defined by formula (I) or (II) featuring R1 as carboxylic acid, salts, or esters; R3 as N-linked triazole or other specified heterocyclic structures with defined substitutions; R4 as NHC(O) with selected alkyl, haloalkyl, or cycloalkyl groups; and R6, R7, R8 as independently selected hydroxyl, amino, alkyl, alkoxy, or related functional groups.
Pharmaceutical composition comprising formula (I) compounds
A pharmaceutical composition containing an effective amount of a formula (I), (II), (III) or (IIIa) compound or pharmaceutically acceptable salt with pharmaceutically acceptable carriers or excipients suitable for treating viral infections.
Method of treating viral diseases using formula (I) compounds
A method of treating diseases caused by parainfluenza virus (including hPIV-1, 2, and 3) in a patient by administering an effective amount of a formula (I) compound.
Use of formula (I) compounds for manufacturing medicaments
Use of compounds of formula (I), (II), (III) or (IIIa) or their pharmaceutically effective salts in the manufacture of medicaments for treating viral infections caused by parainfluenza viruses.
Method of modulating viral haemagglutinin and/or neuraminidase enzymes
A method involving contacting a parainfluenza viral haemagglutinin and/or neuraminidase enzyme with a compound of formula (I), optionally to inhibit the enzyme's activity.
The claims collectively cover novel chemical compounds with defined structural features, their pharmaceutical compositions and uses in treating viral infections, and methods for modulating viral enzyme activities, particularly targeting parainfluenza viruses.
Stated Advantages
The compounds demonstrate significantly enhanced potency against viral haemagglutinin and neuraminidase activities compared to prior art inhibitors, enabling improved antiviral efficacy.
Compounds accommodate dynamic protein loops, such as the flexible 216 loop in hPIV-3 haemagglutinin-neuraminidase, offering a novel binding mode not previously exploited.
The inhibitors exhibit effective antiviral activity in various cell types, including human and monkey kidney cells, and demonstrate low cytotoxicity.
Documented Applications
Treatment or prophylaxis of diseases, disorders, or conditions caused by viral infections such as influenza types A, B, and C and human parainfluenza virus types 1, 2, 3, and 4.
Use in inhibiting haemagglutinin and/or neuraminidase enzymatic activity of parainfluenza and influenza viruses to prevent viral infection and propagation.
Preparation of pharmaceutical compositions for administration to humans or domestic and livestock animals to combat viral infections.
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