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  1. AU="Cecilia Hognon"
  2. AU="Mason, Jeremy K."
  3. AU=Hasumi Hisashi
  4. AU="Swati Sethi"
  5. AU="Martin G. Myers, Jr."
  6. AU="Marcus-Sekura, Carol"
  7. AU="Petagine, Lucy"
  8. AU="Jessa R. Alexander"
  9. AU=Rauner Martina
  10. AU="Richlen, Mindy L"
  11. AU="Merghani, Nada M"
  12. AU=Splitt M P
  13. AU="Zlatanović, Gordana"

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  1. Artikel ; Online: Staring at the Naked Goddess

    Cécilia Hognon / Antonio Monari

    Molecules, Vol 26, Iss 3986, p

    Unraveling the Structure and Reactivity of Artemis Endonuclease Interacting with a DNA Double Strand

    2021  Band 3986

    Abstract: Artemis is an endonuclease responsible for breaking hairpin DNA strands during immune system adaptation and maturation as well as the processing of potentially toxic DNA lesions. Thus, Artemis may be an important target in the development of anticancer ... ...

    Abstract Artemis is an endonuclease responsible for breaking hairpin DNA strands during immune system adaptation and maturation as well as the processing of potentially toxic DNA lesions. Thus, Artemis may be an important target in the development of anticancer therapy, both for the sensitization of radiotherapy and for immunotherapy. Despite its importance, its structure has been resolved only recently, and important questions concerning the arrangement of its active center, the interaction with the DNA substrate, and the catalytic mechanism remain unanswered. In this contribution, by performing extensive molecular dynamic simulations, both classically and at the hybrid quantum mechanics/molecular mechanics level, we evidenced the stable interaction modes of Artemis with a model DNA strand. We also analyzed the catalytic cycle providing the free energy profile and key transition states for the DNA cleavage reaction.
    Schlagwörter Artemis endonuclease ; DNA lesion repair ; classical molecular dynamics ; quantum mechanics/molecular mechanics ; reaction free energy profiles ; Organic chemistry ; QD241-441
    Thema/Rubrik (Code) 612
    Sprache Englisch
    Erscheinungsdatum 2021-06-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  2. Artikel ; Online: Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease

    Cécilia Hognon / Marco Marazzi / Cristina García-Iriepa

    International Journal of Molecular Sciences, Vol 23, Iss 5855, p

    2022  Band 5855

    Abstract: Inhibition of the papain-like protease (PLpro) of SARS-CoV-2 has been demonstrated to be a successful target to prevent the spreading of the coronavirus in the infected body. In this regard, covalent inhibitors, such as the recently proposed VIR251 ... ...

    Abstract Inhibition of the papain-like protease (PLpro) of SARS-CoV-2 has been demonstrated to be a successful target to prevent the spreading of the coronavirus in the infected body. In this regard, covalent inhibitors, such as the recently proposed VIR251 ligand, can irreversibly inactivate PLpro by forming a covalent bond with a specific residue of the catalytic site (Cys 111 ), through a Michael addition reaction. An inhibition mechanism can therefore be proposed, including four steps: (i) ligand entry into the protease pocket; (ii) Cys 111 deprotonation of the thiol group by a Brønsted–Lowry base; (iii) Cys 111 -S − addition to the ligand; and (iv) proton transfer from the protonated base to the covalently bound ligand. Evaluating the energetics and PLpro conformational changes at each of these steps could aid the design of more efficient and selective covalent inhibitors. For this aim, we have studied by means of MD simulations and QM/MM calculations the whole mechanism. Regarding the first step, we show that the inhibitor entry in the PLpro pocket is thermodynamically favorable only when considering the neutral Cys 111 , that is, prior to the Cys 111 deprotonation. For the second step, MD simulations revealed that His 272 would deprotonate Cys 111 after overcoming an energy barrier of ca. 32 kcal/mol (at the QM/MM level), but implying a decrease of the inhibitor stability inside the protease pocket. This information points to a reversible Cys 111 deprotonation, whose equilibrium is largely shifted toward the neutral Cys 111 form. Although thermodynamically disfavored, if Cys 111 is deprotonated in close proximity to the vinylic carbon of the ligand, then covalent binding takes place in an irreversible way (third step) to form the enolate intermediate. Finally, due to Cys 111 -S − negative charge redistribution over the bound ligand, proton transfer from the initially protonated His 272 is favored, finally leading to an irreversibly modified Cys 111 and a restored His 272 . These results elucidate the selectivity ...
    Schlagwörter SARS-CoV-2 ; papain-like protease ; covalent inhibitor ; molecular dynamics ; free energy calculations ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Thema/Rubrik (Code) 333
    Sprache Englisch
    Erscheinungsdatum 2022-05-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  3. Artikel ; Online: Revealing the Molecular Interactions between Human ACE2 and the Receptor Binding Domain of the SARS-CoV-2 Wild-Type, Alpha and Delta Variants

    Cécilia Hognon / Emmanuelle Bignon / Antonio Monari / Marco Marazzi / Cristina Garcia-Iriepa

    International Journal of Molecular Sciences, Vol 24, Iss 2517, p

    2023  Band 2517

    Abstract: After a sudden and first spread of the pandemic caused by the novel SARS-CoV-2 (Severe Acute Respiratory Syndrome—Coronavirus 2) wild-type strain, mutants have emerged which have been associated with increased infectivity, inducing surges in the ... ...

    Abstract After a sudden and first spread of the pandemic caused by the novel SARS-CoV-2 (Severe Acute Respiratory Syndrome—Coronavirus 2) wild-type strain, mutants have emerged which have been associated with increased infectivity, inducing surges in the contagions. The first of the so-called variants of concerns, was firstly isolated in the United Kingdom and later renamed Alpha variant. Afterwards, in the middle of 2021, a new variant appeared called Delta. The latter is characterized by the presence of point mutations in the Spike protein of SARS-CoV-2, especially in the Receptor Binding Domain (RBD). When in its active conformation, the RBD can interact with the human receptor Angiotensin-Converting Enzyme 2 (ACE2) to allow the entry of the virions into cells. In this contribution, by using extended all-atom molecular dynamic simulations, complemented with machine learning post-processing, we analyze the changes in the molecular interaction network induced by these different strains in comparison with the wild-type. On one hand, although relevant variations are evidenced, only limited changes in the global stability indicators and in the flexibility profiles have been observed. On the other hand, key differences were obtained by tracking hydrophilic and hydrophobic molecular interactions, concerning both positioning at the ACE2/RBD interface and formation/disruption dynamic behavior.
    Schlagwörter SARS-CoV-2 ; Alpha variant ; Delta variant ; molecular dynamics ; ACE2/RBD complex formation ; protein-protein interactions ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2023-01-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  4. Artikel ; Online: Never Cared for What They Do

    Tom Miclot / Cécilia Hognon / Emmanuelle Bignon / Alessio Terenzi / Stéphanie Grandemange / Giampaolo Barone / Antonio Monari

    Molecules, Vol 27, Iss 3256, p

    High Structural Stability of Guanine-Quadruplexes in the Presence of Strand-Break Damage

    2022  Band 3256

    Abstract: DNA integrity is an important factor that assures genome stability and, more generally, the viability of cells and organisms. In the presence of DNA damage, the normal cell cycle is perturbed when cells activate their repair processes. Although efficient, ...

    Abstract DNA integrity is an important factor that assures genome stability and, more generally, the viability of cells and organisms. In the presence of DNA damage, the normal cell cycle is perturbed when cells activate their repair processes. Although efficient, the repair system is not always able to ensure complete restoration of gene integrity. In these cases, mutations not only may occur, but the accumulation of lesions can either lead to carcinogenesis or reach a threshold that induces apoptosis and programmed cell death. Among the different types of DNA lesions, strand breaks produced by ionizing radiation are the most toxic due to the inherent difficultly of repair, which may lead to genomic instability. In this article we show, by using classical molecular simulation techniques, that compared to canonical double-helical B-DNA, guanine-quadruplex (G4) arrangements show remarkable structural stability, even in the presence of two strand breaks. Since G4-DNA is recognized for its regulatory roles in cell senescence and gene expression, including oncogenes, this stability may be related to an evolutionary cellular response aimed at minimizing the effects of ionizing radiation.
    Schlagwörter guanine quadruplexes ; DNA strand breaks ; molecular modeling and simulation ; Organic chemistry ; QD241-441
    Thema/Rubrik (Code) 612
    Sprache Englisch
    Erscheinungsdatum 2022-05-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  5. Buch ; Online: Thermodynamics of the interaction between the spike protein of severe acute respiratory syndrome- coronavirus-2 and the receptor of human angiotensin converting enzyme 2. Effects of possible ligands

    Cristina Garcia-Iriepa / Cecilia Hognon / Antonio Francés-Monerris / Isabel Iriepa / Tom Miclot / Giampaolo Barone / Antonio Monari / Marco Marazzi

    2020  

    Abstract: Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community. Human Angiotensin-Converting Enzyme 2 (ACE2) was recently ... ...

    Abstract Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community. Human Angiotensin-Converting Enzyme 2 (ACE2) was recently recognized as the transmembrane protein serving as SARS-CoV-2 entry point into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the complex and of the effects of possible ligands. Moreover, binding free energy between ACE2 and the active Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is evaluated quantitatively, assessing the molecular mechanisms at the basis of the recognition and the ligand-induced decreased affinity. These results boost the knowledge on the molecular grounds of the SARS-CoV-2 infection and allow to suggest rationales useful for the subsequent rational molecular design to treat severe COVID-19 cases.
    Schlagwörter Computational Chemistry and Modeling ; Biophysical Chemistry ; Structure ; SARS-CoV-2 ; ACE2 receptor ; molecular dynamics ; protein-protein interactions ; covid19
    Thema/Rubrik (Code) 612
    Erscheinungsdatum 2020-04-27T05:32:13Z
    Dokumenttyp Buch ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  6. Buch ; Online: Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent

    Antonio Francés-Monerris / Cristina Garcia-Iriepa / Isabel Iriepa / Cecilia Hognon / Tom Miclot / Giampaolo Barone / Antonio Monari / Marco Marazzi

    2020  

    Abstract: The novel SARS-CoV-2 coronavirus is causing a devastating pandemic in 2020, threatening public health in many countries. An unprecedented rapid and global response has been set in motion to identify efficient antiviral agents against SARS-CoV-2, mostly ... ...

    Abstract The novel SARS-CoV-2 coronavirus is causing a devastating pandemic in 2020, threatening public health in many countries. An unprecedented rapid and global response has been set in motion to identify efficient antiviral agents against SARS-CoV-2, mostly relying on the repurposing of drugs presenting or not previously known antiviral activity. Ivermectin is an approved drug used as antiparasitic in humans and animals with well documented broad-spectrum antiviral properties that emerge from host-directed effects. Recent results reported by Wagstaff and coworkers (Antiviral Research 2020 , 178 , 104787) show a potent inhibition of SARS-CoV-2 replication in vitro by ivermectin, and clinical trials with human volunteers have already started. However, the mode of action of ivermectin is still largely unknown, especially at the molecular level. Here, we employ advanced molecular dynamics simulations to assess the influence of ivermectin on several key viral protein targets, with the aim to reveal the molecular bases of antiviral mechanisms against SARS-CoV-2. Interestingly, we show that ivermectin could be regarded as a multitarget agent, inhibiting different viral functions. These include blocking the recognition by the SARS-CoV-2 Receptor Binding Domain (RBD) of the Angiotensin-Converting Enzyme 2 (ACE2), the interactions with the two viral proteases 3CL pro and PL pro , and the SARS Unique Domain (SUD) non-structural protein. Hence, the wide spectrum of actions involving i) the interference with cell infection, ii) the inhibition of viral replication, and iii) elusion of the host immune system, could point to an unprecedented synergy between host- and virus-directed effects explaining the high anti-SARS-CoV-2 activity observed for this compound.
    Schlagwörter Biophysics ; Chemical Biology ; COVID-19 ; ACE2 ; SARS Unique Domain ; Proteases ; Molecular Dynamics ; Ivermectin ; covid19
    Thema/Rubrik (Code) 572
    Erscheinungsdatum 2020-08-10T13:05:50Z
    Dokumenttyp Buch ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  7. Artikel: Thermodynamics of the interaction between the spike protein of severe acute respiratory syndrome- coronavirus-2 and the receptor of human angiotensin converting enzyme 2. Effects of possible ligands (preprint)

    Cristina, Garcia-Iriepa Cecilia Hognon Antonio Francés-Monerris Isabel Iriepa Tom Miclot Giampaolo Barone Antonio Monari Marco Marazzi

    Abstract: Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community Human Angiotensin-Converting Enzyme 2 (ACE2) was recently ... ...

    Abstract Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community Human Angiotensin-Converting Enzyme 2 (ACE2) was recently recognized as the transmembrane protein serving as SARS-CoV-2 entry point into cells, thus constituting the first biomolecular event leading to COVID-19 disease Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the complex and of the effects of possible ligands Moreover, binding free energy between ACE2 and the active Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is evaluated quantitatively, assessing the molecular mechanisms at the basis of the recognition and the ligand-induced decreased affinity These results boost the knowledge on the molecular grounds of the SARS-CoV-2 infection and allow to suggest rationales useful for the subsequent rational molecular design to treat severe COVID-19 cases
    Schlagwörter covid19
    Verlag WHO
    Dokumenttyp Artikel
    Anmerkung WHO #Covidence: #2297
    Datenquelle COVID19

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