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Viruses ; 13(10)2021 10 02.
Article in English | MEDLINE | ID: covidwho-1441885


Viral proteases are indispensable for successful virion maturation, thus making them a prominent drug target. Their enzyme activity is tightly spatiotemporally regulated by expression in the precursor form with little or no activity, followed by activation via autoprocessing. These cleavage events are frequently triggered upon transportation to a specific compartment inside the host cell. Typically, precursor oligomerization or the presence of a co-factor is needed for activation. A detailed understanding of these mechanisms will allow ligands with non-canonical mechanisms of action to be designed, which would specifically modulate the initial irreversible steps of viral protease autoactivation. Binding sites exclusive to the precursor, including binding sites beyond the protease domain, can be exploited. Both inhibition and up-regulation of the proteolytic activity of viral proteases can be detrimental for the virus. All these possibilities are discussed using examples of medically relevant viruses including herpesviruses, adenoviruses, retroviruses, picornaviruses, caliciviruses, togaviruses, flaviviruses, and coronaviruses.

Antiviral Agents/pharmacology , Viral Protease Inhibitors/pharmacology , Viral Proteases/metabolism , Virus Diseases/drug therapy , Adenoviruses, Human/drug effects , Adenoviruses, Human/metabolism , Flavivirus/drug effects , Flavivirus/metabolism , HIV-1/drug effects , Herpesviridae/drug effects , Herpesviridae/metabolism , Humans , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Viral Proteases/biosynthesis
Viruses ; 13(8)2021 08 12.
Article in English | MEDLINE | ID: covidwho-1436097


Type III interferons (lambda IFNs) are a quite new, small family of three closely related cytokines with interferon-like activity. Attention to IFN-λ is mainly focused on direct antiviral activity in which, as with IFN-α, viral genome replication is inhibited without the participation of immune system cells. The heterodimeric receptor for lambda interferons is exposed mainly on epithelial cells, which limits its possible action on other cells, thus reducing the likelihood of developing undesirable side effects compared to type I IFN. In this study, we examined the antiviral potential of exogenous human IFN-λ1 in cellular models of viral infection. To study the protective effects of IFN-λ1, three administration schemes were used: 'preventive' (pretreatment); 'preventive/therapeutic' (pre/post); and 'therapeutic' (post). Three IFN-λ1 concentrations (from 10 to 500 ng/mL) were used. We have shown that human IFN-λ1 restricts SARS-CoV-2 replication in Vero cells with all three treatment schemes. In addition, we have shown a decrease in the viral loads of CHIKV and IVA with the 'preventive' and 'preventive/therapeutic' regimes. No significant antiviral effect of IFN-λ1 against AdV was detected. Our study highlights the potential for using IFN-λ as a broad-spectrum therapeutic agent against respiratory RNA viruses.

Adenoviruses, Human/drug effects , Chikungunya virus/drug effects , Influenza A virus/drug effects , Interferons/pharmacology , SARS-CoV-2/drug effects , A549 Cells , Adenoviruses, Human/physiology , Animals , Chikungunya virus/physiology , Chlorocebus aethiops , Dose-Response Relationship, Drug , Gene Expression Regulation , Humans , Influenza A virus/physiology , Interferons/therapeutic use , Interleukins , RNA Virus Infections/drug therapy , RNA Virus Infections/prevention & control , Recombinant Proteins/pharmacology , SARS-CoV-2/physiology , Vero Cells , Viral Load/drug effects , Virus Replication/drug effects
Int J Mol Sci ; 22(18)2021 Sep 17.
Article in English | MEDLINE | ID: covidwho-1430892


Previous studies reported on the broad-spectrum antiviral function of heparin. Here we investigated the antiviral function of magnesium-modified heparin and found that modified heparin displayed a significantly enhanced antiviral function against human adenovirus (HAdV) in immortalized and primary cells. Nuclear magnetic resonance analyses revealed a conformational change of heparin when complexed with magnesium. To broadly explore this discovery, we tested the antiviral function of modified heparin against herpes simplex virus type 1 (HSV-1) and found that the replication of HSV-1 was even further decreased compared to aciclovir. Moreover, we investigated the antiviral effect against the new severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and measured a 55-fold decreased viral load in the supernatant of infected cells associated with a 38-fold decrease in virus growth. The advantage of our modified heparin is an increased antiviral effect compared to regular heparin.

Antiviral Agents/pharmacology , Heparin/pharmacology , Magnesium Chloride/pharmacology , Acyclovir/pharmacology , Adenoviruses, Human/drug effects , Adenoviruses, Human/physiology , Animals , Antiviral Agents/chemistry , CHO Cells , Cell Line, Tumor , Chlorocebus aethiops , Cricetulus , Drug Evaluation, Preclinical , Fibroblasts , Heparin/chemistry , Herpesvirus 1, Human/drug effects , Herpesvirus 1, Human/physiology , Humans , Magnesium Chloride/chemistry , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Structure , Primary Cell Culture , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Structure-Activity Relationship , Vero Cells , Viral Load/drug effects , Virus Replication/drug effects