Biology subjects

Khatun, O.

Publications and source records attributed to Khatun, O..

7 recordsLinked to original sources

bioRxiv2026

Small molecule inhibition of the mitochondrial lipid transfer protein STARD7 attenuates influenza viral replication

The increasing appearance of drug-resistant and zoonotic influenza strains highlights an urgent need for host-directed antivirals that offer broad-spectrum activity and a higher barrier to resistance. Here, we describe the characterization of M4, a small-molecule identified from a high-thoughput screen that potently inhibits influenza A and B viruses. Mechanistic studies reveal that M4 suppresses replication by causing nuclear retention of the viral ribonucleoprotein (vRNP) complex. Chemoproteomic profiling identified the lipid transfer protein STARD7 as the primary cellular target, and genetic depletion of STARD7 phenocopies the antiviral effects of M4. Additional studies localizes the M4 binding site to cysteine 302 within the lipid-binding domain of STARD7, supporting a model in which STARD7-dependent lipid transfer activity promotes efficient vRNP trafficking and nuclear export. Combining M4 with baloxavir enhances antiviral efficacy in a murine infection model, providing in vivo support for a host-directed strategy. Together, these results identify STARD7 as a metabolic checkpoint licensing vRNP export and establish a proof of concept for therapeutic intervention with small molecule inhibitors. Author SummaryInfluenza viruses continue to cause widespread illness and pose an ongoing pandemic threat, in part because existing antiviral drugs can lose effectiveness as the virus evolves resistance. To address this challenge, we focused on identifying therapies that target host cell processes required for viral replication, rather than viral proteins themselves. In this study, we describe a small molecule, M4, that inhibits replication of both influenza A and B viruses by blocking a critical step in the viral life cycle. We found that M4 acts on a host protein called STARD7, which helps move certain lipids to the right places inside cells. When STARD7 is inhibited, the influenza viral ribonucleoprotein (vRNP) complex becomes trapped in the cell nucleus and cannot reach the cytoplasm, preventing the virus from completing its replication cycle. Disrupting STARD7 genetically produces the same effect, confirming that this host protein is important for influenza replication. These findings point to a previously unrecognized host gating mechanism that controls nuclear export of the vRNP complex during infection. Although M4 alone showed limited activity in animals, combining it with an existing antiviral drug strongly improved antiviral efficacy. Together, our results reveal a new host pathway that influenza viruses rely on and support host-directed combination approaches to strengthen antiviral treatment and help counter drug resistance.

microbiology↗

bioRxiv2025

An Oral Combination therapy against SARS-CoV-2 based on Synergistic Action of Auranofin and Remdesivir.

The combination of direct-acting and host-directed antivirals targeting SARS-CoV-2 represents an attractive treatment strategy to combat COVID-19. In our previous work, we showed that the FDA-approved anti-arthritis drug Auranofin restricts SARS-CoV-2 replication and pathology in an animal model. Here, we report that Auranofin inhibits SARS-CoV-2 by targeting viral entry and main protease (Mpro) activity without affecting viral transcription. Time-of-addition studies combined with functional assays of viral entry, protease activity, and cell-cell fusion delineated its inhibitory effects at both early and late stages of the viral life cycle. Molecular docking and isothermal titration calorimetry analyses of Auranofin and the known Mpro inhibitor Nirmatrelvir indicated competitive binding within the Mpro active-site pocket. In addition, Auranofin attenuated NF-{kappa}B-dependent signalling and suppressed proinflammatory cytokine production. Combination studies with SARS-CoV-2 targeting nucleoside analogues, revealed the strongest synergistic antiviral activity with remdesivir in vitro. Comparable synergy was observed between auranofin and GS-621763, the orally bioavailable derivative of remdesivir, and was further validated in a preclinical animal model. Collectively, these findings provide a rationale for the further development of auranofin-nucleoside analog combinations targeting SARS-CoV-2. FundingThis research has been supported by ICMR (IIRPIG-2023-0000978) and BIRAC grant (BT/CS0070/06/22) to ST. We acknowledge the infrastructure and research support provided to IISc by the Crypto Relief Fund, L&T Trust, DST-FIST program, Institute of Eminence Fund, Ministry of Education, and the DBT-IISc partnership program (Phase II). RN acknowledges DBT-RA fellowship, SK acknowledges PMRF fellowship, and RS acknowledges FICCI-PMRF fellowship. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSMultiple previous studies have provided evidence showing that auranofin is an antiviral agent targeting SARS-CoV-2 through a host-targeting mechanism, involving the inhibition of thioredoxin reductase and redox homeostasis. Mixed results have been reported regarding the effect of this drug on inhibiting virus-induced syncytia. A prior study from our lab demonstrated the drugs effectiveness in reducing SARS-CoV-2 viral loads in both cell and animal models. Added value of the studyOur study firmly establishes the synergistic use of Auranofin and Remdesivir GS 621763 in the treatment of SARS-CoV-2 infection.

microbiology↗

bioRxiv2023

SARS-CoV-2 Nsp13 is a viral RHIM protein promoting cell death linked to Z-RNA sensing and ZBP1-RIPK3 signaling

RHIM is a protein motif in cell death proteins that assembles higher-order signaling complexes and triggers regulated cell death, which in itself limits virus spread and additionally triggers inflammation for mounting immune responses. A few DNA viruses employ viral RHIMs mimicking host RHIMs. However, these viral RHIMs counteract host cell death by interacting with host RHIM proteins and blocking complex formation to alleviate antiviral defenses. Whether RNA viruses operate such viral RHIMs remains unknown. RHIM-protein signaling promotes lung damage and cytokine storm in respiratory RNA virus infections, arguing the presence of viral RHIMs. Here, we report the novel viral RHIMs in Nsp13 and Nsp14 of SARS-CoV-2 and other bat RNA viruses, providing the basis for bats as the hosts for their evolution. Nsp13 promoted cell death in bat and human cells, however, viral RHIM of Nsp13 is more critical for human cell death than bat cells, suggesting species-specific regulation. The conformation of RNA-binding channel in Nsp13 is critical for cell death in bat and human cells. Nsp13 showed RHIM-dependent interactions with ZBP1 and RIPK3 and promoted the formation of large insoluble complexes of ZBP1 and RIPK3. Also, Nsp13 promoted ZBP1-RIPK3 signaling-mediated cell death dependent on intracellular RNA ligands. Intriguingly, the SARS-CoV-2 genome consists of bona fide Z-RNA-forming segments. These SARS-CoV-2 Z-RNA segments promoted Nsp13-dependent cell death, further revealing Nsp13s association with Z-RNA sensing and ZBP1-RIPK3 signaling. Our findings reveal the functional viral RHIMs of bat-originated RNA viruses regulating host cell death associated with Z-RNA sensing and ZBP1-RIPK3 signaling activation. These observations allow the understanding of mechanisms of cellular damage and cytokine storm in SARS-CoV-2 and other bat-originated RNA virus infections. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/554434v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@f71c5aorg.highwire.dtl.DTLVardef@1666aa5org.highwire.dtl.DTLVardef@e37d82org.highwire.dtl.DTLVardef@145020f_HPS_FORMAT_FIGEXP M_FIG C_FIG One-sentence summaryBat-associated RNA viruses employ viral RHIMs and regulate host cell death.

immunology↗

bioRxiv2023

SARS-CoV-2 variants of concern exhibit differential gastro-intestinal tropism and pathogenesis in the Syrian golden hamster model.

Severe Acute Respiratory Syndrome Virus-2 (SARS-CoV-2) is a respiratory virus that uses angiotensin-converting enzyme 2 (ACE2) protein as an entry receptor. Thus, ACE2 expression levels in different tissues should dictate viral tropism. Notably, human ACE2 mRNA and protein levels are most abundant in the gastrointestinal tract, a pattern mirrored in Syrian golden hamsters. This prompted us to investigate the gastrointestinal tropism of SARS-CoV-2 variants of concern, including the Wuhan-like Hong Kong strain, highly pathogenic Delta, and highly transmissible but mildly pathogenic Omicron variants in hamsters. Delta was the most pathogenic in the respiratory and gastrointestinal tracts, followed by ancestral Wuhan-like and Omicron strains. In the gastrointestinal tract, viral RNA load was significant in the proximal organs such as the oesophagus and stomach, highest in the SI, and minimal to undetectable in the colon. Additionally, all three variants reduced fecal microbial diversity, with the Delta causing the highest decrease in observed features and phylogenetic diversity. Our findings highlight Deltas stronger preference for the gastrointestinal tract, suggesting a link between high virulence and gastrointestinal tropism of SARS-CoV-2 variants of concern.

pathology↗

bioRxiv2022

ORF6 protein of SARS-CoV-2 inhibits TRIM25 mediated RIG-I ubiquitination to mitigate type I IFN induction.

Evasion and antagonism of host cellular immunity upon SARS-CoV-2 infection confers a profound replication advantage on the virus and contributes to COVID-19 pathogenesis. We explored the ability of different SARS-CoV-2 proteins to antagonize the host innate immune system and found that the ORF6 protein mitigated type-I IFN (interferon) induction and downstream IFN signaling. Our findings also corroborated previous reports that ORF6 blocks the nuclear import of IRF3 and STAT1 to inhibit IFN induction and signaling. Here we show that ORF6 directly interacts with RIG-I and blocks downstream type-I IFN induction and signaling by inhibiting K-63 linked ubiquitination of RIG-I by the E3 Ligase TRIM25. This involves ORF6-mediated targeting of TRIM25 for degradation, also observed during SARS-CoV-2 infection. The type-I IFN antagonistic activity of ORF6 was mapped to its C-terminal cytoplasmic tail, specifically to amino acid residues 52-61. Overall, we provide new insights into how the SARS-CoV-2 ORF6 protein inhibits type I-IFN induction and signaling through distinct mechanisms.

microbiology↗

bioRxiv2022

A natural broad-spectrum inhibitor of enveloped virus entry, effective against SARS-CoV-2 and Influenza A Virus in preclinical animal models.

The COVID-19 pandemic has highlighted the need for novel antivirals for pandemic management and preparedness. Targeting host processes that are co-opted by viruses is an attractive strategy for developing antivirals with a high resistance barrier. Picolinic acid (PA) is a byproduct of tryptophan metabolism, endogenously produced in humans and other mammals. Here we report broad-spectrum antiviral effects of PA against enveloped viruses, including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), Influenza A virus (IAV), Flaviviruses, Herpes Simplex Virus, and Human Parainfluenza Virus. We further demonstrate using animal models that PA is effective against SARS-CoV-2 and IAV, especially as an oral prophylactic. The mode of action studies revealed that PA inhibits viral entry of enveloped viruses, primarily by interfering with viral-cellular membrane fusion, inhibiting virus-mediated syncytia formation, and dysregulating cellular endocytosis. Overall, our data establish PA as a broad-spectrum antiviral agent, with promising preclinical efficacy against pandemic viruses SARS-CoV-2 and IAV.

microbiology↗

bioRxiv2021

Meta-analysis of orthogonal OMICs data from COVID-19 patients unveils prognostic markers and antiviral factors.

While our battle with the COVID-19 pandemic continues, a multitude of Omics data has been generated from patient samples in various studies, which remains to be translated. We conducted a meta-analysis of published transcriptome and proteome profiles of nasal swab and bronchioalveolar lavage fluid (BALF) samples of COVID-19 patients, to shortlist high confidence upregulated host factors. Subsequently, mRNA overexpression of selected genes was validated in nasal swab/BALF samples from a cohort of COVID-19 positive/negative, symptomatic/asymptomatic individuals. Analysis of these data revealed S100 family genes (S100A6, S100A8, S100A9, and S100P) as prognostic markers of COVID-19 disease. Furthermore, Thioredoxin gene (TXN) was identified as a significant upregulated host factor in our overlap analysis. An FDA-approved drug Auranofin, which inhibits Thioredoxin reduction, was found to mitigate SARS-CoV-2 replication in vitro and in vivo in the hamster challenge model. Overall, this study translates COVID-19 host response Big Data into potential clinical interventions.

microbiology↗