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Identification of an indol-based derivative as potent and selective varicella zoster virus (VZV) inhibitor.

ABSTRACT: We report the synthesis and antiviral activity of a new family of non-nucleoside antivirals, derived from the indole nucleus. Modifications of this template through Mannich and Friedel-Crafts reactions, coupled with nucleophilic displacement and reductive aminations led to 23 final derivatives, which were pharmacologically tested. Tryptamine derivative 17a was found to have a selective inhibitory activity against human varicella zoster virus (VZV) replication in vitro, being inactive against a variety of other DNA and RNA viruses. A structure-activity relationship (SAR) study showed that the presence of a biphenyl ethyl moiety and the acetylation at the amino group of tryptamine are a prerequisite for anti-VZV activity. The novel compound shows the same activity against thymidine kinase (TK)-competent (TK⁺) and TK-deficient (TK^-) VZV strains, pointing to a novel mechanism of antiviral action.

SUBMITTER: Musella S

PROVIDER: S-EPMC7115581 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Immune regulation of alphaherpesvirus latency and reactivation is critical for the control of virus pathogenesis. This is evident for herpes simplex virus 1 (HSV-1), where cytotoxic T lymphocytes (CTLs) prevent viral reactivation independent of apoptosis induction. This inhibition of HSV-1 reactivation has been attributed to granzyme B cleavage of HSV infected cell protein 4 (ICP4); however, it is unknown whether granzyme B cleavage of ICP4 can directly protect cells from CTL cytotoxicity. Varicella zoster virus (VZV) is closely related to HSV-1; however, it is unknown whether VZV proteins contain granzyme B cleavage sites. Natural killer (NK) cells play a central role in VZV and HSV-1 pathogenesis and, like CTLs, utilize granzyme B to kill virally infected target cells. However, whether alphaherpesvirus granzyme B cleavage sites could modulate NK cell-mediated cytotoxicity has yet to be established. This study aimed to identify novel HSV-1 and VZV gene products with granzyme B cleavage sites and assess whether they could protect cells from NK cell-mediated cytotoxicity. We have demonstrated that HSV ICP27, VZV open reading frame 62 (ORF62), and VZV ORF4 are cleaved by granzyme B. However, in an NK cell cytotoxicity assay, only VZV ORF4 conferred protection from NK cell-mediated cytotoxicity. The granzyme B cleavage site in ORF4 was identified via site-directed mutagenesis and, surprisingly, the mutation of this cleavage site did not alter the ability of ORF4 to modulate NK cell cytotoxicity, suggesting that ORF4 has a novel immunoevasive function that is independent from the granzyme B cleavage site.IMPORTANCE HSV-1 causes oral and genital herpes and establishes life-long latency in sensory ganglia. HSV-1 reactivates multiple times in a person's life and can cause life-threatening disease in immunocompromised patients. VZV is closely related to HSV-1, causes chickenpox during primary infection, and establishes life-long latency in ganglia, from where it can reactivate to cause herpes zoster (shingles). Unlike HSV-1, VZV only infects humans, and there are limited model systems; thus, little is known concerning how VZV maintains latency and why VZV reactivates. Through studying the link between immune cell cytotoxic functions, granzyme B, and viral gene products, an increased understanding of viral pathogenesis will be achieved.

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Identification of an indol-based derivative as potent and selective varicella zoster virus (VZV) inhibitor.

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