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Background: Chikungunya virus (CHIKV) has reemerged as a major public health concern, causing chikungunya fever with increasing cases and neurological complications. Methods: In the present study, we investigated a low-passage human isolate of the East/ Central/South African (ECSA) lineage of CHIKV strain LK(EH)CH6708, which exhibited a mix of small and large viral plaques. The small and large plaque variants were isolated and designated as CHIKV-SP and CHIKV-BP, respectively. CHIKV-SP and CHIKV-BP were characterized in vitro and in vivo to compare their virus production and virulence. Additionally, whole viral genome analysis and reverse genetics were employed to identify genomic virulence factors. Results: CHIKV-SP demonstrated lower virus production in mammalian cells and attenuated virulence in a murine model. On the other hand, CHIKV-BP induced higher pro-inflammatory cytokine levels, compromised the integrity of the blood–brain barrier, and led to astrocyte infection in mouse brains. Furthermore, the CHIKV-SP variant had limited transmission potential in Aedesalbopictus mosquitoes, likely due to restricted dissemination. Whole viral genome analysis revealed multiple genetic mutations in the CHIKV-SP variant, including a Glycine (G) to Arginine (R) mutation at position 55 in the viral E2 glycoprotein. Reverse genetics experiments confirmed that the E2-G55R mutation alone was sufficient to reduce virus production in vitro and virulence in mice. Conclusions: These findings highlight the attenuating effects of the E2-G55R mutation on CHIKV pathogenicity and neurovirulence and emphasize the importance of monitoring this mutation in natural infections. [ABSTRACT FROM AUTHOR]

Over the years, the hand, foot and mouth disease (HFMD) has sparked epidemics across many countries which mainly affected young children. While symptoms are usually mild, severe complications may arise, and some even lead to death. Such concerns, coupled with the lack of approved vaccines and antivirals to date, create an urgency in the identification of safe therapeutics against HFMD. The disease is mainly transmitted by enteroviruses like enterovirus A71 (EV-A71). Essential for enterovirus replication is the host protein, PI4KB. In this study, we investigate the antiviral efficacy of a novel PI4KB inhibitor, CUR-N399. We found that CUR-N399 displayed broad-spectrum antiviral activity against picornaviruses in cell culture models. Using a suckling mouse model of lethal EV-A71 infection, CUR-N399 was found to be well-tolerated, promote survival and reduce viral titre in mice organs. Together, these support the discovery of CUR-N399 as an antiviral against EV-A71 and potentially other closely related viruses. • There are currently no approved treatments and vaccines for Enterovirus A71. • CUR-N399 displays broad-spectrum antiviral effects in vitro, against viruses in the Picornaviridae family. • CUR-N399 increases survival in a lethal suckling mouse model of EV-A71 infection. • A corresponding reduction in viral titre in the limb and brain is observed upon treatment with CUR-N399. • Antiviral effects of CUR-N399 can be attributed to its inhibition of PI4KB, a host protein essential for viral replication. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has brought about unprecedented medical and healthcare challenges worldwide. With the continual emergence and spread of new COVID-19 variants, four drug compound libraries were interrogated for their antiviral activities against SARS-CoV-2. Here, we show that the drug screen has resulted in 121 promising anti-SARS-CoV-2 compounds, of which seven were further shortlisted for hit validation: citicoline, pravastatin sodium, tenofovir alafenamide, imatinib mesylate, calcitriol, dexlansoprazole, and prochlorperazine dimaleate. In particular, the active form of vitamin D, calcitriol, exhibits strong potency against SARS-CoV-2 on cell-based assays and is shown to work by modulating the vitamin D receptor pathway to increase antimicrobial peptide cathelicidin expression. However, the weight, survival rate, physiological conditions, histological scoring, and virus titre between SARS-CoV-2 infected K18-hACE2 mice pre-treated or post-treated with calcitriol were negligible, indicating that the differential effects of calcitriol may be due to differences in vitamin D metabolism in mice and warrants future investigation using other animal models. [ABSTRACT FROM AUTHOR]