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  1. Article ; Online: Picolinic acid is a broad-spectrum inhibitor of enveloped virus entry that restricts SARS-CoV-2 and influenza A virus in vivo.

    Narayan, Rohan / Sharma, Mansi / Yadav, Rajesh / Biji, Abhijith / Khatun, Oyahida / Kaur, Sumandeep / Kanojia, Aditi / Joy, Christy Margrat / Rajmani, Raju / Sharma, Pallavi Raj / Jeyasankar, Sharumathi / Rani, Priya / Shandil, Radha Krishan / Narayanan, Shridhar / Rao, Durga Chilakalapudi / Satchidanandam, Vijaya / Das, Saumitra / Agarwal, Rachit / Tripathi, Shashank

    Cell reports. Medicine

    2023  Volume 4, Issue 8, Page(s) 101127

    Abstract: The COVID-19 pandemic highlights an urgent need for effective antivirals. Targeting host processes co-opted by viruses is an attractive antiviral strategy with a high resistance barrier. Picolinic acid (PA) is a tryptophan metabolite endogenously ... ...

    Abstract The COVID-19 pandemic highlights an urgent need for effective antivirals. Targeting host processes co-opted by viruses is an attractive antiviral strategy with a high resistance barrier. Picolinic acid (PA) is a tryptophan metabolite endogenously produced in mammals. Here, we report the broad-spectrum antiviral activity of PA against enveloped viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus (IAV), flaviviruses, herpes simplex virus, and parainfluenza virus. Mechanistic studies reveal that PA inhibits enveloped virus entry by compromising viral membrane integrity, inhibiting virus-cellular membrane fusion, and interfering with cellular endocytosis. More importantly, in pre-clinical animal models, PA exhibits promising antiviral efficacy against SARS-CoV-2 and IAV. Overall, our data establish PA as a broad-spectrum antiviral with promising pre-clinical efficacy against pandemic viruses SARS-CoV-2 and IAV.
    MeSH term(s) Animals ; Humans ; SARS-CoV-2/metabolism ; COVID-19 ; Influenza A virus ; Virus Internalization ; Pandemics ; Virus Replication ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Mammals/metabolism
    Chemical Substances picolinic acid (QZV2W997JQ) ; Antiviral Agents
    Language English
    Publishing date 2023-07-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2666-3791
    ISSN (online) 2666-3791
    DOI 10.1016/j.xcrm.2023.101127
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Identification of COVID-19 prognostic markers and therapeutic targets through meta-analysis and validation of Omics data from nasopharyngeal samples.

    Biji, Abhijith / Khatun, Oyahida / Swaraj, Shachee / Narayan, Rohan / Rajmani, Raju S / Sardar, Rahila / Satish, Deepshikha / Mehta, Simran / Bindhu, Hima / Jeevan, Madhumol / Saini, Deepak K / Singh, Amit / Gupta, Dinesh / Tripathi, Shashank

    EBioMedicine

    2021  Volume 70, Page(s) 103525

    Abstract: Background: While our battle with the COVID-19 pandemic continues, a multitude of Omics data have been generated from patient samples in various studies. Translation of these data into clinical interventions against COVID-19 remains to be accomplished. ... ...

    Abstract Background: While our battle with the COVID-19 pandemic continues, a multitude of Omics data have been generated from patient samples in various studies. Translation of these data into clinical interventions against COVID-19 remains to be accomplished. Exploring host response to COVID-19 in the upper respiratory tract can unveil prognostic markers and therapeutic targets.
    Methods: We conducted a meta-analysis of published transcriptome and proteome profiles of respiratory samples of COVID-19 patients to shortlist high confidence upregulated host factors. Subsequently, mRNA overexpression of selected genes was validated in nasal swabs from a cohort of COVID-19 positive/negative, symptomatic/asymptomatic individuals. Guided by this analysis, we sought to check for potential drug targets. An FDA-approved drug, Auranofin, was tested against SARS-CoV-2 replication in cell culture and Syrian hamster challenge model.
    Findings: The meta-analysis and validation in the COVID-19 cohort revealed S100 family genes (S100A6, S100A8, S100A9, and S100P) as prognostic markers of severe COVID-19. Furthermore, Thioredoxin (TXN) was found to be consistently upregulated. Auranofin, which targets Thioredoxin reductase, was found to mitigate SARS-CoV-2 replication in vitro. Furthermore, oral administration of Auranofin in Syrian hamsters in therapeutic as well as prophylactic regimen reduced viral replication, IL-6 production, and inflammation in the lungs.
    Interpretation: Elevated mRNA level of S100s in the nasal swabs indicate severe COVID-19 disease, and FDA-approved drug Auranofin mitigated SARS-CoV-2 replication in preclinical hamster model.
    Funding: This study was supported by the DBT-IISc partnership program (DBT (IED/4/2020-MED/DBT)), the Infosys Young Investigator award (YI/2019/1106), DBT-BIRAC grant (BT/CS0007/CS/02/20) and the DBT-Wellcome Trust India Alliance Intermediate Fellowship (IA/I/18/1/503613) to ST lab.
    MeSH term(s) Adult ; Animals ; Biomarkers/metabolism ; COVID-19/genetics ; COVID-19/pathology ; COVID-19/virology ; Cell Line ; Chlorocebus aethiops ; Cohort Studies ; Female ; HEK293 Cells ; Humans ; Inflammation/genetics ; Inflammation/virology ; Interleukin-6/genetics ; Male ; Mesocricetus ; Middle Aged ; Nasopharynx/pathology ; Nasopharynx/virology ; Pandemics ; Prognosis ; Proteome/genetics ; RNA, Messenger/genetics ; SARS-CoV-2/pathogenicity ; Transcriptome/genetics ; Up-Regulation/genetics ; Vero Cells ; Virus Replication/genetics
    Chemical Substances Biomarkers ; Interleukin-6 ; Proteome ; RNA, Messenger
    Language English
    Publishing date 2021-08-12
    Publishing country Netherlands
    Document type Journal Article ; Meta-Analysis
    ZDB-ID 2851331-9
    ISSN 2352-3964
    ISSN (online) 2352-3964
    DOI 10.1016/j.ebiom.2021.103525
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Identification of COVID-19 prognostic markers and therapeutic targets through meta-analysis and validation of Omics data from nasopharyngeal samples

    Abhijith Biji / Oyahida Khatun / Shachee Swaraj / Rohan Narayan / Raju S. Rajmani / Rahila Sardar / Deepshikha Satish / Simran Mehta / Hima Bindhu / Madhumol Jeevan / Deepak K. Saini / Amit Singh / Dinesh Gupta / Shashank Tripathi

    EBioMedicine, Vol 70, Iss , Pp 103525- (2021)

    2021  

    Abstract: Background: While our battle with the COVID-19 pandemic continues, a multitude of Omics data have been generated from patient samples in various studies. Translation of these data into clinical interventions against COVID-19 remains to be accomplished. ... ...

    Abstract Background: While our battle with the COVID-19 pandemic continues, a multitude of Omics data have been generated from patient samples in various studies. Translation of these data into clinical interventions against COVID-19 remains to be accomplished. Exploring host response to COVID-19 in the upper respiratory tract can unveil prognostic markers and therapeutic targets. Methods: We conducted a meta-analysis of published transcriptome and proteome profiles of respiratory samples of COVID-19 patients to shortlist high confidence upregulated host factors. Subsequently, mRNA overexpression of selected genes was validated in nasal swabs from a cohort of COVID-19 positive/negative, symptomatic/asymptomatic individuals. Guided by this analysis, we sought to check for potential drug targets. An FDA-approved drug, Auranofin, was tested against SARS-CoV-2 replication in cell culture and Syrian hamster challenge model. Findings: The meta-analysis and validation in the COVID-19 cohort revealed S100 family genes (S100A6, S100A8, S100A9, and S100P) as prognostic markers of severe COVID-19. Furthermore, Thioredoxin (TXN) was found to be consistently upregulated. Auranofin, which targets Thioredoxin reductase, was found to mitigate SARS-CoV-2 replication in vitro. Furthermore, oral administration of Auranofin in Syrian hamsters in therapeutic as well as prophylactic regimen reduced viral replication, IL-6 production, and inflammation in the lungs. Interpretation: Elevated mRNA level of S100s in the nasal swabs indicate severe COVID-19 disease, and FDA-approved drug Auranofin mitigated SARS-CoV-2 replication in preclinical hamster model. Funding: This study was supported by the DBT-IISc partnership program (DBT (IED/4/2020-MED/DBT)), the Infosys Young Investigator award (YI/2019/1106), DBT-BIRAC grant (BT/CS0007/CS/02/20) and the DBT-Wellcome Trust India Alliance Intermediate Fellowship (IA/I/18/1/503613) to ST lab.
    Keywords COVID-19 ; Nasal swab/BALF ; Transcriptome ; Proteome ; Meta-analysis ; Prognostic marker ; Medicine ; R ; Medicine (General) ; R5-920
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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

    Narayan, Rohan / Sharma, Mansi / Yadav, Rajesh Thangavel / Biji, Abhijith / Khatun, Oyahida / Rajmani, Raju S / Sharma, Pallavi Raj / Jeyashankar, Sharumathi / Rani, Priya / Rao, C. Durga / Satchidanandam, Vijaya / Das, Saumitra / Agarwal, Rachit / Tripathi, Shashank

    bioRxiv

    Abstract: 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. ... ...

    Abstract 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.
    Keywords covid19
    Language English
    Publishing date 2022-02-17
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2022.02.16.480801
    Database COVID19

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  5. Article ; Online: Meta-analysis of orthogonal OMICs data from COVID-19 patients unveils prognostic markers and antiviral factors.

    Biji, Abhijith / Swaraj, Shachee / Khatun, Oyahida / Narayan, Rohan / Sardar, Rahila / Satish, Deepshikha / Mehta, Simran / Bindhu, Hima / Jeevan, Madhumol / Saini, Deepak Kumar / Singh, Amit / Gupta, Dinesh / Tripathi, Shashank

    bioRxiv

    Abstract: Coronavirus disease 2019 (COVID-19) pandemic has lasted more than a year since its first case in December 2019 and yet its social and economic burden continues to grow. While a tremendous amount of OMICs data has been generated from COVID-19 patient ... ...

    Abstract Coronavirus disease 2019 (COVID-19) pandemic has lasted more than a year since its first case in December 2019 and yet its social and economic burden continues to grow. While a tremendous amount of OMICs data has been generated from COVID-19 patient samples, the host antiviral response and markers of disease progression remain to be completely delineated. In this study, we have conducted a meta-analysis of published transcriptome and proteome profiles of the nasal swab and bronchioalveolar lavage fluid (BALF) samples of COVID-19 patients to identify high confidence upregulated host factors. This was followed by rank ordering, shortlisting, and validation of overexpression of a set of host factors in a nasal swab/BALF samples from a cohort of COVID-19 positive/negative, symptomatic/asymptomatic individuals. This led to the identification of host antiviral response in the upper respiratory tract and potential prognostic markers. Notably, SEPRIN B3 and Thioredoxin were identified as potential antiviral factors. In addition, several S100 family proteins were found to be upregulated in COVID-19 specific and disease severity dependent manner. Overall, this study provides novel insights into the host antiviral mechanisms and COVID-19 disease progression.
    Keywords covid19
    Language English
    Publishing date 2021-02-18
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2021.02.18.431825
    Database COVID19

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