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  1. Article ; Online: A mechanistic insight on how Compromised Hydrolysis of Triacylglycerol 7 (CHT7) restrains the involvement of it's CXC domain from quiescence repression.

    Chauhan, Manisha / Arshi, Syeda Amna / Narayanan, Naveen / Arfin, Haseeb Ul / Sharma, Amit

    International journal of biological macromolecules

    2024  Volume 265, Issue Pt 1, Page(s) 130844

    Abstract: CHT7 is a regulator of quiescence repression in Chlamydomonas reinhardtii. Initially, CHT7's repression activity was thought to be managed by its DNA-binding CXC domain. Later, it was found that the CHT7-CXC domain is dispensable for CHT7's activities. ... ...

    Abstract CHT7 is a regulator of quiescence repression in Chlamydomonas reinhardtii. Initially, CHT7's repression activity was thought to be managed by its DNA-binding CXC domain. Later, it was found that the CHT7-CXC domain is dispensable for CHT7's activities. Rather, CHT7's predicted protein domains were proposed to be involved in regulation activities by binding to other repressors in the cell. Yet, it remains unclear why and how CHT7 refrains its CXC domain from participating in any transcriptional activities. The question becomes more intriguing, since CXC binding regions are available in promoter regions of some of the misregulated genes in CHT7 mutant (cht7). Through biophysical experiments and molecular dynamics approaches, we studied the DNA recognition behavior of CHT7-CXC. The results indicate that this domain possesses sequence selectivity due to the differential binding abilities of its subdomains. Further, to understand if the case is that CXC loses its DNA binding capabilities in the vicinity of other repressors, we examined CHT7-CXC's DNA binding stability under the spatial constraint conditions created through fusing CHT7-CXC with AsLOV2. The results show limited ability of CHT7-CXC to withstand steric forces and provide insights to why and how algal cells may hold back CHT7-CXC's indulgence in quiescence repression. CLASSIFICATIONS: Biological Sciences, Biophysics and Computational Biology.
    MeSH term(s) Triglycerides ; Hydrolysis ; Transcription Factors/genetics ; DNA-Binding Proteins/metabolism ; DNA ; Transcription, Genetic
    Chemical Substances Triglycerides ; Transcription Factors ; DNA-Binding Proteins ; DNA (9007-49-2)
    Language English
    Publishing date 2024-03-13
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2024.130844
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Ritonavir may inhibit exoribonuclease activity of nsp14 from the SARS-CoV-2 virus and potentiate the activity of chain terminating drugs

    Narayanan, Naveen / Nair, Deepak T

    International journal of biological macromolecules. 2021 Jan. 31, v. 168

    2021  

    Abstract: SARS-CoV-2is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3′ to 5′ exoribonuclease activity responsible for removing mismatches that arise during genome ...

    Abstract SARS-CoV-2is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3′ to 5′ exoribonuclease activity responsible for removing mismatches that arise during genome duplication. A homology model of nsp10-nsp14 complex was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp14. This exercise showed that ritonavir might bind to the exoribonuclease active site of the nsp14 protein. A model of the SARS-CoV-2-nsp10-nsp14 complex bound to substrate RNA showed that the ritonavir binding site overlaps with that of the 3′ nucleotide of substrate RNA. A comparison of the calculated energies of binding for RNA and ritonavir suggested that the drug may bind to the active site of nsp14 with significant affinity. It is, therefore, possible that ritonavir may prevent association with substrate RNA and thus inhibit the exoribonuclease activity of nsp14. Overall, our computational studies suggest that ritonavir may serve as an effective inhibitor of the nsp14 protein. nsp14 is known to attenuate the inhibitory effect of drugs that function through premature termination of viral genome replication. Hence, ritonavir may potentiate the therapeutic properties of drugs such as remdesivir, favipiravir and ribavirin.
    Keywords COVID-19 infection ; RNA ; Severe acute respiratory syndrome coronavirus 2 ; active sites ; antiretroviral agents ; binding sites ; computer simulation ; enzyme activity ; enzyme inhibition ; enzyme inhibitors ; exoribonucleases ; gene duplication ; sequence homology ; viral genome ; viral nonstructural proteins
    Language English
    Dates of publication 2021-0131
    Size p. 272-278.
    Publishing place Elsevier B.V.
    Document type Article
    Note golden set
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2020.12.038
    Database NAL-Catalogue (AGRICOLA)

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  3. Article ; Online: Vitamin B12 may inhibit RNA-dependent-RNA polymerase activity of nsp12 from the SARS-CoV-2 virus.

    Narayanan, Naveen / Nair, Deepak T

    IUBMB life

    2020  Volume 72, Issue 10, Page(s) 2112–2120

    Abstract: SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. Like other members of this family, the virus possesses a positive-sense single-stranded RNA genome. The genome encodes for the nsp12 ... ...

    Abstract SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. Like other members of this family, the virus possesses a positive-sense single-stranded RNA genome. The genome encodes for the nsp12 protein, which houses the RNA-dependent-RNA polymerase (RdRP) activity responsible for the replication of the viral genome. A homology model of nsp12 was prepared using the structure of the SARS nsp12 (6NUR) as a model. The model was used to carry out in silico screening to identify molecules among natural products, or Food and Drug Administration-approved drugs that can potentially inhibit the activity of nsp12. This exercise showed that vitamin B12 (methylcobalamin) may bind to the active site of the nsp12 protein. A model of the nsp12 in complex with substrate RNA and incoming NTP showed that vitamin B12 binding site overlaps with that of the incoming nucleotide. A comparison of the calculated energies of binding for RNA plus NTP and methylcobalamin suggested that the vitamin may bind to the active site of nsp12 with significant affinity. It is, therefore, possible that methylcobalamin binding may prevent association with RNA and NTP and thus inhibit the RdRP activity of nsp12. Overall, our computational studies suggest that methylcobalamin form of vitamin B12 may serve as an effective inhibitor of the nsp12 protein.
    MeSH term(s) Amino Acid Sequence ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Binding Sites ; Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors ; Coronavirus RNA-Dependent RNA Polymerase/chemistry ; Coronavirus RNA-Dependent RNA Polymerase/genetics ; Coronavirus RNA-Dependent RNA Polymerase/metabolism ; Genome, Viral ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Prescription Drugs/chemistry ; Prescription Drugs/pharmacology ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; SARS-CoV-2/genetics ; Sequence Alignment ; Sequence Homology, Amino Acid ; Substrate Specificity ; Thermodynamics ; User-Computer Interface ; Vitamin B 12/chemistry ; Vitamin B 12/pharmacology
    Chemical Substances Antiviral Agents ; Prescription Drugs ; Coronavirus RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; NSP12 protein, SARS-CoV-2 (EC 2.7.7.48) ; Vitamin B 12 (P6YC3EG204)
    Keywords covid19
    Language English
    Publishing date 2020-08-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1492141-8
    ISSN 1521-6551 ; 1521-6543
    ISSN (online) 1521-6551
    ISSN 1521-6543
    DOI 10.1002/iub.2359
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Ritonavir may inhibit exoribonuclease activity of nsp14 from the SARS-CoV-2 virus and potentiate the activity of chain terminating drugs.

    Narayanan, Naveen / Nair, Deepak T

    International journal of biological macromolecules

    2020  Volume 168, Page(s) 272–278

    Abstract: SARS-CoV-2is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3' to 5' exoribonuclease activity responsible for removing mismatches that arise during genome ...

    Abstract SARS-CoV-2is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3' to 5' exoribonuclease activity responsible for removing mismatches that arise during genome duplication. A homology model of nsp10-nsp14 complex was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp14. This exercise showed that ritonavir might bind to the exoribonuclease active site of the nsp14 protein. A model of the SARS-CoV-2-nsp10-nsp14 complex bound to substrate RNA showed that the ritonavir binding site overlaps with that of the 3' nucleotide of substrate RNA. A comparison of the calculated energies of binding for RNA and ritonavir suggested that the drug may bind to the active site of nsp14 with significant affinity. It is, therefore, possible that ritonavir may prevent association with substrate RNA and thus inhibit the exoribonuclease activity of nsp14. Overall, our computational studies suggest that ritonavir may serve as an effective inhibitor of the nsp14 protein. nsp14 is known to attenuate the inhibitory effect of drugs that function through premature termination of viral genome replication. Hence, ritonavir may potentiate the therapeutic properties of drugs such as remdesivir, favipiravir and ribavirin.
    MeSH term(s) Amino Acid Sequence ; Antiviral Agents/administration & dosage ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; COVID-19/drug therapy ; COVID-19/virology ; Catalytic Domain ; Computer Simulation ; Drug Evaluation, Preclinical ; Drug Synergism ; Drug Therapy, Combination ; Exoribonucleases/antagonists & inhibitors ; Exoribonucleases/chemistry ; Exoribonucleases/genetics ; Genome, Viral/drug effects ; Humans ; Molecular Dynamics Simulation ; Pandemics ; Ritonavir/administration & dosage ; Ritonavir/chemistry ; Ritonavir/pharmacology ; SARS-CoV-2/drug effects ; SARS-CoV-2/genetics ; SARS-CoV-2/physiology ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/genetics ; Virus Replication/drug effects
    Chemical Substances Antiviral Agents ; Viral Nonstructural Proteins ; Exoribonucleases (EC 3.1.-) ; NSP14 protein, SARS-CoV-2 (EC 3.1.-) ; Ritonavir (O3J8G9O825)
    Language English
    Publishing date 2020-12-09
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2020.12.038
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Book ; Online: Ritonavir May Inhibit Exoribonuclease Activity of Nsp14 from the SARS-CoV-2 Virus and Potentiate the Activity of Chain Terminating Drugs

    naveen narayanan / deepak nair

    2020  

    Abstract: SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3’ to 5’ exoribonuclease activity responsible for removing mismatches that arise during ... ...

    Abstract SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3’ to 5’ exoribonuclease activity responsible for removing mismatches that arise during genome duplication. A homology model of nsp10-nsp14 complex was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp14. This exercise showed that ritonavir might bind to the exoribonuclease active site of the nsp14 protein. A model of the SCV2-nsp10-nsp14 complex bound to substrate RNA showed that the ritonavir binding site overlaps with that of the 3’ nucleotide of substrate RNA. A comparison of the calculated energies of binding for RNA and ritonavir suggested that the drug may bind to the active site of nsp14 with significant affinity. It is, therefore, possible that ritonavir may prevent association with substrate RNA and thus inhibit the exoribonuclease activity of nsp14. Overall, our computational studies suggest that ritonavir may serve as an effective inhibitor of the nsp14 protein. nsp14 is known to attenuate the inhibitory effect of drugs that function through premature termination of viral genome replication. Hence, ritonavir may potentiate the therapeutic properties of drugs such as remdesivir, favipiravir and ribavirin.
    Keywords Biochemistry ; Bioinformatics and Computational Biology ; nsp14 ; exoribonuclease ; SARS-CoV-2 ; inhibitor ; ritonavir ; covid19
    Publishing date 2020-05-13T05:42:40Z
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Vitamin B12 may inhibit RNA‐dependent‐RNA polymerase activity of nsp12 from the SARS‐CoV ‐2 virus

    Narayanan, Naveen / Nair, Deepak T.

    IUBMB Life

    2020  Volume 72, Issue 10, Page(s) 2112–2120

    Keywords Clinical Biochemistry ; Genetics ; Cell Biology ; Biochemistry ; Molecular Biology ; covid19
    Language English
    Publisher Wiley
    Publishing country us
    Document type Article ; Online
    ZDB-ID 1492141-8
    ISSN 1521-6551 ; 1521-6543
    ISSN (online) 1521-6551
    ISSN 1521-6543
    DOI 10.1002/iub.2359
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Antiviral therapeutics directed against RNA dependent RNA polymerases from positive-sense viruses.

    Bhatia, Sonam / Narayanan, Naveen / Nagpal, Shilpi / Nair, Deepak T

    Molecular aspects of medicine

    2021  Volume 81, Page(s) 101005

    Abstract: Viruses with positive-sense single stranded RNA (+ssRNA) genomes are responsible for different diseases and represent a global health problem. In addition to developing new vaccines that protect against severe illness on infection, it is imperative to ... ...

    Abstract Viruses with positive-sense single stranded RNA (+ssRNA) genomes are responsible for different diseases and represent a global health problem. In addition to developing new vaccines that protect against severe illness on infection, it is imperative to identify new antiviral molecules to treat infected patients. The genome of these RNA viruses generally codes for an enzyme with RNA dependent RNA polymerase (RdRP) activity. This molecule is centrally involved in the duplication of the RNA genome. Inhibition of this enzyme by small molecules will prevent duplication of the RNA genome and thus reduce the viral titer. An overview of the different therapeutic strategies used to inhibit RdRPs from +ssRNA viruses is provided, along with an analysis of these enzymes to highlight new binding sites for inhibitors.
    MeSH term(s) Antiviral Agents/therapeutic use ; Humans ; RNA Viruses/drug effects ; RNA Viruses/genetics ; RNA-Dependent RNA Polymerase/antagonists & inhibitors ; RNA-Dependent RNA Polymerase/genetics
    Chemical Substances Antiviral Agents ; RNA-Dependent RNA Polymerase (EC 2.7.7.48)
    Language English
    Publishing date 2021-07-24
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 197640-0
    ISSN 1872-9452 ; 0098-2997
    ISSN (online) 1872-9452
    ISSN 0098-2997
    DOI 10.1016/j.mam.2021.101005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: The proofreading activity of Pfprex from Plasmodium falciparum can prevent mutagenesis of the apicoplast genome by oxidized nucleotides.

    Sharma, Minakshi / Narayanan, Naveen / Nair, Deepak T

    Scientific reports

    2020  Volume 10, Issue 1, Page(s) 11157

    Abstract: The DNA polymerase module of the Pfprex enzyme (PfpPol) is responsible for duplication of the genome of the apicoplast organelle in the malaria parasite. We show that PfpPol can misincorporate oxidized nucleotides such as 8oxodGTP opposite dA. This event ...

    Abstract The DNA polymerase module of the Pfprex enzyme (PfpPol) is responsible for duplication of the genome of the apicoplast organelle in the malaria parasite. We show that PfpPol can misincorporate oxidized nucleotides such as 8oxodGTP opposite dA. This event gives rise to transversion mutations that are known to lead to adverse physiological outcomes. The apicoplast genome is particularly vulnerable to the harmful effects of 8oxodGTP due to very high AT content (~ 87%). We show that the proofreading activity of PfpPol has the unique ability to remove the oxidized nucleotide from the primer terminus. Due to this property, the proofreading domain of PfpPol is able to prevent mutagenesis of the AT-rich apicoplast genome and neutralize the deleterious genotoxic effects of ROS generated in the apicoplast due to normal metabolic processes. The proofreading activity of the Pfprex enzyme may, therefore, represent an attractive target for therapeutic intervention. Also, a survey of DNA repair pathways shows that the observed property of Pfprex constitutes a novel form of dynamic error correction wherein the repair of promutagenic damaged nucleotides is concomitant with DNA replication.
    MeSH term(s) Apicoplasts/genetics ; Apicoplasts/metabolism ; DNA Repair ; Deoxyguanine Nucleotides/metabolism ; Genome, Protozoan/genetics ; Multienzyme Complexes/metabolism ; Multienzyme Complexes/physiology ; Mutagenesis/genetics ; Nucleotides/metabolism ; Oxidation-Reduction ; Plasmodium falciparum/genetics ; Plasmodium falciparum/metabolism ; Protozoan Proteins/metabolism ; Protozoan Proteins/physiology
    Chemical Substances Deoxyguanine Nucleotides ; Multienzyme Complexes ; Nucleotides ; Protozoan Proteins ; prex protein, Plasmodium falciparum ; 8-oxodeoxyguanosine triphosphate (139307-94-1)
    Language English
    Publishing date 2020-07-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-67853-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Book ; Online: Ritonavir may inhibit exoribonuclease activity of nsp14 from the SARS-CoV-2 virus and potentiate the activity of chain terminating drugs

    narayanan, naveen / nair, deepak t

    2020  

    Abstract: SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3’ to 5’exoribonuclease activity responsible for removing mismatches that arise during genome ...

    Abstract SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3’ to 5’exoribonuclease activity responsible for removing mismatches that arise during genome duplication. A homology model of nsp10-nsp14 complex was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp14. This exercise showed that ritonavir might bind to the exoribonuclease active site of the nsp14 protein. A model of the SCV2-nsp10-nsp14 complex bound to substrate RNA showed that the ritonavir binding site overlaps with that of the 3’nucleotide of substrate RNA. A comparison of the calculated energies of binding for RNA and ritonavir suggested that the drug may bind to the active site of nsp14 with significant affinity. It is, therefore, possible that ritonavir may prevent association with substrate RNA and thus inhibit the exoribonuclease activity of nsp14. Overall, our computational studies suggest that ritonavirmay serve as an effective inhibitor of the nsp14 protein. nsp14 is known to attenuate the inhibitory effect of drugs that function through premature termination of viral genome replication. Hence, ritonavir may potentiate the therapeutic properties of drugs such as remdesivir, favipiravir and ribavirin.
    Keywords covid19
    Publisher Center for Open Science
    Publishing country us
    Document type Book ; Online
    DOI 10.35543/osf.io/f5gnq
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Book ; Online: Vitamin B12 may inhibit RNA-dependent-RNA polymerase activity of nsp12 from the COVID-19 Virus

    nair, deepak t / narayanan, naveen

    2020  

    Abstract: COVID-19 is the causative agent for the ongoing pandemic, and this virus belongs to the Coronaviridae family. Like other members of this family, the virus possesses a positive-sense single-stranded RNA genome. The genome encodes for the nsp12 protein, ... ...

    Abstract COVID-19 is the causative agent for the ongoing pandemic, and this virus belongs to the Coronaviridae family. Like other members of this family, the virus possesses a positive-sense single-stranded RNA genome. The genome encodes for the nsp12 protein, which houses the RNA-dependent-RNA polymerase (RdRP) activity responsible for the replication of the viral genome. A homology model of nsp12 was prepared using the structure of the SARS nsp12 (6NUR) as a model. The model was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp12. This exercise showed that vitamin B12 (methylcobalamin) may bind to the active site of the nsp12 protein. A model of the nsp12 in complex with substrate RNA and incoming NTP showed that Vitamin B12 binding site overlaps with that of the incoming nucleotide. A comparison of the calculated energies of binding for RNA plus NTP and methylcobalamin suggested that the vitamin may bind to the active site of nsp12 with significant affinity. It is, therefore, possible that methylcobalamin binding may prevent association with RNA and NTP and thus inhibit the RdRP activity of nsp12. Overall, our computational studies suggest that methylcobalamin form of vitamin B12 may serve as an effective inhibitor of the nsp12 protein.
    Keywords covid19
    Publisher Center for Open Science
    Publishing country us
    Document type Book ; Online
    DOI 10.35543/osf.io/p48fa
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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