Abstract
Human adenovirus infections can develop into diffuse multi-organ diseases in young children and immunocompromised patients, and severe cases can lead to death. However, there are no approved antiviral drugs available to treat adenovirus diseases. In this study, a chemiluminescence-based, high-throughput screening (HTS) assay was developed and applied to screen human adenovirus 5(HAdV5)inhibitors from 1,813 approved drug library and 556 traditional Chinese medicine-sourced small-molecule compounds. We identified three compounds with in vitro anti-HAdV5 activities in the low-micromolar range (EC50 values 0.3-4.5 μM, selectivity index values 20-300) that also showed inhibitory effects on HAdV3. Cardamomin (CDM) had good anti-HAdV5 activity in vitro. Furthermore, three dilutions of CDM (150, 75, and 37.5 mg/kg/d) administered to BALB/c mouse models inhibited HAdV5-fluc infection at 1 day post-infection by 80% (p < 0.05), 76% (p < 0.05), and 58% (p < 0.05), respectively. HE-staining of pathological tissue sections of mice infected with a wildtype adenoviral strain showed that CDM had a protective effect on tissues, especially in the liver, and greatly inhibited virus-induced necrosis of liver tissue. Thus, CDM inhibits adenovirus replication in vivo and in vitro. This study established a high-throughput screening method for anti-HAdV5 drugs and demonstrated CDM to be a candidate for HAdV5 therapy, potentially providing a new treatment for patients infected with adenoviruses.
Highlights
Adenoviruses, which were first discovered in 1953, are unencapsulated double-stranded DNA viruses that can cause zoonotic acute infectious diseases
We developed a chemiluminescence-based highthroughput screening (HTS) assay for the discovery of human adenovirus 5(HAdV5) antiviral inhibitors and screened a library of 1,813 FDA-approved drugs and 556 traditional Chinese medicine-sourced small molecule compounds
The high-throughput screening (HTS) conditions of cell-seeding density and HAdV5 dose were optimized at 30,000 cells/well and 1 × 103 PFU/well, respectively
Summary
Adenoviruses, which were first discovered in 1953, are unencapsulated double-stranded DNA viruses that can cause zoonotic acute infectious diseases. They usually invade the respiratory system, digestive system, urinary system, or nervous system and cause a number of diseases (Dhingra et al, 2019). Adenovirus infections are globally distributed and may occur in any season. Since their discovery, adenovirus outbreaks have been reported both in China and abroad. China has not yet established a nationwide epidemiological surveillance program for adenovirus infections, and the CDC is unable to detect or provide early outbreak warnings (Bailey et al, 2018)
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