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  1. Article: Proline/Glycine residues of the PG-levels guide conformational changes along the transport cycle in the mitochondrial carnitine/acylcarnitine carrier (SLC25A20)

    Giangregorio, Nicola / Pierri, Ciro Leonardo / Tonazzi, Annamaria / Incampo, Giovanna / Tragni, Vincenzo / De Grassi, Anna / Indiveri, Cesare

    International journal of biological macromolecules. 2022 Nov. 30, v. 221

    2022  

    Abstract: Mitochondrial carnitine/acylcarnitine carrier (CAC) is a member of the mitochondrial carrier (MC) family and imports acylcarnitine into the mitochondrial matrix in exchange for carnitine, playing a pivotal role in carnitine shuttle, crucial for fatty ... ...

    Abstract Mitochondrial carnitine/acylcarnitine carrier (CAC) is a member of the mitochondrial carrier (MC) family and imports acylcarnitine into the mitochondrial matrix in exchange for carnitine, playing a pivotal role in carnitine shuttle, crucial for fatty acid oxidation. The crystallized structure of CAC has not been solved yet, however, the availability of several in vitro/in silico studies, also based on the crystallized structures of the ADP/ATP carrier in the cytosolic-conformation and in the matrix-conformation, has made possible to confirm the hypothesis of the single-binding centered-gated pore mechanism for all the members of the MC family. In addition, our recent bioinformatics analyses allowed quantifying in silico the importance of protein residues of MC substrate binding region, of those involved in the formation of the matrix and cytosolic gates, and of those belonging to the Pro/Gly (PG) levels, proposed to be crucial for the tilting/kinking/bending of the six MC transmembrane helices, funneling the substrate translocation pathway. Here we present a combined in silico/in vitro analysis employed for investigating the role played by a group of 6 proline residues and 6 glycine residues, highly conserved in CAC, belonging to MC PG-levels. Residues of the PG-levels surround the similarly located MC common substrate binding region, and were proposed to lead conformational changes and substrate translocation, following substrate binding. For our analysis, we employed 3D molecular modeling approaches, alanine scanning site-directed mutagenesis and in vitro transport assays. Our analysis reveals that P130 (H3), G268 (H6) and G220 (H5), mutated in alanine, affect severely CAC transport activity (mutant catalytic efficiency lower than 5 % compared to the wild type CAC), most likely due to their major role in triggering CAC conformational changes, following carnitine binding. Notably, P30A (H1) and G121A (H3) CAC mutants, increase the carnitine uptake up to 217 % and 112 %, respectively, compared to the wild type CAC.
    Keywords alanine ; beta oxidation ; bioinformatics ; carnitine ; catalytic activity ; computer simulation ; crystallization ; mitochondria ; mutants ; proline ; site-directed mutagenesis
    Language English
    Dates of publication 2022-1130
    Size p. 1453-1465.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2022.09.135
    Database NAL-Catalogue (AGRICOLA)

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  2. Article: Modeling SARS-CoV-2 spike/ACE2 protein-protein interactions for predicting the binding affinity of new spike variants for ACE2, and novel ACE2 structurally related human protein targets, for COVID-19 handling in the 3PM context.

    Tragni, Vincenzo / Preziusi, Francesca / Laera, Luna / Onofrio, Angelo / Mercurio, Ivan / Todisco, Simona / Volpicella, Mariateresa / De Grassi, Anna / Pierri, Ciro Leonardo

    The EPMA journal

    2022  Volume 13, Issue 1, Page(s) 149–175

    Abstract: Aims: The rapid spread of new SARS-CoV-2 variants has highlighted the crucial role played in the infection by mutations occurring at the SARS-CoV-2 spike receptor binding domain (RBD) in the interactions with the human ACE2 receptor. In this context, it ...

    Abstract Aims: The rapid spread of new SARS-CoV-2 variants has highlighted the crucial role played in the infection by mutations occurring at the SARS-CoV-2 spike receptor binding domain (RBD) in the interactions with the human ACE2 receptor. In this context, it urgently needs to develop new rapid tools for quickly predicting the affinity of ACE2 for the SARS-CoV-2 spike RBD protein variants to be used with the ongoing SARS-CoV-2 genomic sequencing activities in the clinics, aiming to gain clues about the transmissibility and virulence of new variants, to prevent new outbreaks and to quickly estimate the severity of the disease in the context of the 3PM.
    Methods: In our study, we used a computational pipeline for calculating the interaction energies at the SARS-CoV-2 spike RBD/ACE2 protein-protein interface for a selected group of characterized infectious variants of concern/interest (VoC/VoI). By using our pipeline, we built 3D comparative models of the SARS-CoV-2 spike RBD/ACE2 protein complexes for the VoC B.1.1.7-United Kingdom (carrying the mutations of concern/interest N501Y, S494P, E484K at the RBD), P.1-Japan/Brazil (RBD mutations: K417T, E484K, N501Y), B.1.351-South Africa (RBD mutations: K417N, E484K, N501Y), B.1.427/B.1.429-California (RBD mutations: L452R), the B.1.141 (RBD mutations: N439K), and the recent B.1.617.1-India (RBD mutations: L452R; E484Q) and the B.1.620 (RBD mutations: S477N; E484K). Then, we used the obtained 3D comparative models of the SARS-CoV-2 spike RBD/ACE2 protein complexes for predicting the interaction energies at the protein-protein interface.
    Results: Along SARS-CoV-2 mutation database screening and mutation localization analysis, it was ascertained that the most dangerous mutations at VoC/VoI spike proteins are located mainly at three regions of the SARS-CoV-2 spike "boat-shaped" receptor binding motif, on the RBD domain. Notably, the P.1 Japan/Brazil variant present three mutations, K417T, E484K, N501Y, located along the entire receptor binding motif, which apparently determines the highest interaction energy at the SARS-CoV-2 spike RBD/ACE2 protein-protein interface, among those calculated. Conversely, it was also observed that the replacement of a single acidic/hydrophilic residue with a basic residue (E484K or N439K) at the "stern" or "bow" regions, of the boat-shaped receptor binding motif on the RBD, appears to determine an interaction energy with ACE2 receptor higher than that observed with single mutations occurring at the "hull" region or with other multiple mutants. In addition, our pipeline allowed searching for ACE2 structurally related proteins, i.e., THOP1 and NLN, which deserve to be investigated for their possible involvement in interactions with the SARS-CoV-2 spike protein, in those tissues showing a low expression of ACE2, or as a novel receptor for future spike variants. A freely available web-tool for the in silico calculation of the interaction energy at the SARS-CoV-2 spike RBD/ACE2 protein-protein interface, starting from the sequences of the investigated spike and/or ACE2 variants, was made available for the scientific community at: https://www.mitoairm.it/covid19affinities.
    Conclusion: In the context of the PPPM/3PM, the employment of the described pipeline through the provided webservice, together with the ongoing SARS-CoV-2 genomic sequencing, would help to predict the transmissibility of new variants sequenced from future patients, depending on SARS-CoV-2 genomic sequencing activities and on the specific amino acid replacement and/or on its location on the SARS-CoV-2 spike RBD, to put in play all the possible counteractions for preventing the most deleterious scenarios of new outbreaks, taking into consideration that a greater transmissibility has not to be necessarily related to a more severe manifestation of the disease.
    Supplementary information: The online version contains supplementary material available at 10.1007/s13167-021-00267-w.
    Language English
    Publishing date 2022-01-06
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2545928-4
    ISSN 1878-5085 ; 1878-5077
    ISSN (online) 1878-5085
    ISSN 1878-5077
    DOI 10.1007/s13167-021-00267-w
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  3. Article ; Online: 3D structures inferred from cDNA clones identify the CD1D-Restricted γδ T cell receptor in dromedaries.

    Linguiti, Giovanna / Tragni, Vincenzo / Pierri, Ciro Leonardo / Massari, Serafina / Lefranc, Marie-Paule / Antonacci, Rachele / Ciccarese, Salvatrice

    Frontiers in immunology

    2022  Volume 13, Page(s) 928860

    Abstract: The Camelidae species occupy an important immunological niche within the humoral as well as cell mediated immune response. Although recent studies have highlighted that the somatic hypermutation (SHM) shapes the T cell receptor gamma (TRG) and delta (TRD) ...

    Abstract The Camelidae species occupy an important immunological niche within the humoral as well as cell mediated immune response. Although recent studies have highlighted that the somatic hypermutation (SHM) shapes the T cell receptor gamma (TRG) and delta (TRD) repertoire in
    MeSH term(s) Animals ; Antigens, CD1d/genetics ; Camelus ; Clone Cells ; Complementarity Determining Regions/genetics ; DNA, Complementary ; Humans ; Receptors, Antigen, T-Cell, gamma-delta/chemistry ; Receptors, Antigen, T-Cell, gamma-delta/genetics
    Chemical Substances Antigens, CD1d ; CD1D protein, human ; Complementarity Determining Regions ; DNA, Complementary ; Receptors, Antigen, T-Cell, gamma-delta
    Language English
    Publishing date 2022-08-09
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2022.928860
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: New Insights Regarding Hemin Inhibition of the Purified Rat Brain 2-Oxoglutarate Carrier and Relationships with Mitochondrial Dysfunction.

    Miniero, Daniela Valeria / Gambacorta, Nicola / Spagnoletta, Anna / Tragni, Vincenzo / Loizzo, Stefano / Nicolotti, Orazio / Pierri, Ciro Leonardo / De Palma, Annalisa

    Journal of clinical medicine

    2022  Volume 11, Issue 24

    Abstract: A kinetic analysis of the transport assays on the purified rat brain 2-oxoglutarate/malate carrier (OGC) was performed starting from our recent results reporting about a competitive inhibitory behavior of hemin, a physiological porphyrin derivative, on ... ...

    Abstract A kinetic analysis of the transport assays on the purified rat brain 2-oxoglutarate/malate carrier (OGC) was performed starting from our recent results reporting about a competitive inhibitory behavior of hemin, a physiological porphyrin derivative, on the OGC reconstituted in an active form into proteoliposomes. The newly provided transport data and the elaboration of the kinetic equations show evidence that hemin exerts a mechanism of partially competitive inhibition, coupled with the formation of a ternary complex hemin-carrier substrate, when hemin targets the OGC from the matrix face. A possible interpretation of the provided kinetic analysis, which is supported by computational studies, could indicate the existence of a binding region responsible for the inhibition of the OGC and supposedly involved in the regulation of OGC activity. The proposed regulatory binding site is located on OGC mitochondrial matrix loops, where hemin could establish specific interactions with residues involved in the substrate recognition and/or conformational changes responsible for the translocation of mitochondrial carrier substrates. The regulatory binding site would be placed about 6 Å below the substrate binding site of the OGC, facing the mitochondrial matrix, and would allow the simultaneous binding of hemin and 2-oxoglutarate or malate to different regions of the carrier. Overall, the presented experimental and computational analyses help to shed light on the possible existence of the hemin-carrier substrate ternary complex, confirming the ability of the OGC to bind porphyrin derivatives, and in particular hemin, with possible consequences for the mitochondrial redox state mediated by the malate/aspartate shuttle led by the mitochondrial carriers OGC and AGC.
    Language English
    Publishing date 2022-12-19
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662592-1
    ISSN 2077-0383
    ISSN 2077-0383
    DOI 10.3390/jcm11247519
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  5. Article ; Online: Proline/Glycine residues of the PG-levels guide conformational changes along the transport cycle in the mitochondrial carnitine/acylcarnitine carrier (SLC25A20).

    Giangregorio, Nicola / Pierri, Ciro Leonardo / Tonazzi, Annamaria / Incampo, Giovanna / Tragni, Vincenzo / De Grassi, Anna / Indiveri, Cesare

    International journal of biological macromolecules

    2022  Volume 221, Page(s) 1453–1465

    Abstract: Mitochondrial carnitine/acylcarnitine carrier (CAC) is a member of the mitochondrial carrier (MC) family and imports acylcarnitine into the mitochondrial matrix in exchange for carnitine, playing a pivotal role in carnitine shuttle, crucial for fatty ... ...

    Abstract Mitochondrial carnitine/acylcarnitine carrier (CAC) is a member of the mitochondrial carrier (MC) family and imports acylcarnitine into the mitochondrial matrix in exchange for carnitine, playing a pivotal role in carnitine shuttle, crucial for fatty acid oxidation. The crystallized structure of CAC has not been solved yet, however, the availability of several in vitro/in silico studies, also based on the crystallized structures of the ADP/ATP carrier in the cytosolic-conformation and in the matrix-conformation, has made possible to confirm the hypothesis of the single-binding centered-gated pore mechanism for all the members of the MC family. In addition, our recent bioinformatics analyses allowed quantifying in silico the importance of protein residues of MC substrate binding region, of those involved in the formation of the matrix and cytosolic gates, and of those belonging to the Pro/Gly (PG) levels, proposed to be crucial for the tilting/kinking/bending of the six MC transmembrane helices, funneling the substrate translocation pathway. Here we present a combined in silico/in vitro analysis employed for investigating the role played by a group of 6 proline residues and 6 glycine residues, highly conserved in CAC, belonging to MC PG-levels. Residues of the PG-levels surround the similarly located MC common substrate binding region, and were proposed to lead conformational changes and substrate translocation, following substrate binding. For our analysis, we employed 3D molecular modeling approaches, alanine scanning site-directed mutagenesis and in vitro transport assays. Our analysis reveals that P130 (H3), G268 (H6) and G220 (H5), mutated in alanine, affect severely CAC transport activity (mutant catalytic efficiency lower than 5 % compared to the wild type CAC), most likely due to their major role in triggering CAC conformational changes, following carnitine binding. Notably, P30A (H1) and G121A (H3) CAC mutants, increase the carnitine uptake up to 217 % and 112 %, respectively, compared to the wild type CAC.
    MeSH term(s) Carnitine Acyltransferases/genetics ; Carnitine Acyltransferases/chemistry ; Carnitine Acyltransferases/metabolism ; Proline ; Glycine ; Carnitine ; Alanine
    Chemical Substances Carnitine Acyltransferases (EC 2.3.1.-) ; acylcarnitine ; Proline (9DLQ4CIU6V) ; Glycine (TE7660XO1C) ; Carnitine (S7UI8SM58A) ; Alanine (OF5P57N2ZX)
    Language English
    Publishing date 2022-09-17
    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.2022.09.135
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Protein structure analysis of the interactions between SARS-CoV-2 spike protein and the human ACE2 receptor: from conformational changes to novel neutralizing antibodies.

    Mercurio, Ivan / Tragni, Vincenzo / Busto, Francesco / De Grassi, Anna / Pierri, Ciro Leonardo

    Cellular and molecular life sciences : CMLS

    2020  Volume 78, Issue 4, Page(s) 1501–1522

    Abstract: The recent severe acute respiratory syndrome, known as Coronavirus Disease 2019 (COVID-19) has spread so much rapidly and severely to induce World Health Organization (WHO) to declare a state of emergency over the new coronavirus SARS-CoV-2 pandemic. ... ...

    Abstract The recent severe acute respiratory syndrome, known as Coronavirus Disease 2019 (COVID-19) has spread so much rapidly and severely to induce World Health Organization (WHO) to declare a state of emergency over the new coronavirus SARS-CoV-2 pandemic. While several countries have chosen the almost complete lock-down for slowing down SARS-CoV-2 spread, the scientific community is called to respond to the devastating outbreak by identifying new tools for diagnosis and treatment of the dangerous COVID-19. With this aim, we performed an in silico comparative modeling analysis, which allows gaining new insights into the main conformational changes occurring in the SARS-CoV-2 spike protein, at the level of the receptor-binding domain (RBD), along interactions with human cells angiotensin-converting enzyme 2 (ACE2) receptor, that favor human cell invasion. Furthermore, our analysis provides (1) an ideal pipeline to identify already characterized antibodies that might target SARS-CoV-2 spike RBD, aiming to prevent interactions with the human ACE2, and (2) instructions for building new possible neutralizing antibodies, according to chemical/physical space restraints and complementary determining regions (CDR) mutagenesis of the identified existing antibodies. The proposed antibodies show in silico high affinity for SARS-CoV-2 spike RBD and can be used as reference antibodies also for building new high-affinity antibodies against present and future coronaviruses able to invade human cells through interactions of their spike proteins with the human ACE2. More in general, our analysis provides indications for the set-up of the right biological molecular context for investigating spike RBD-ACE2 interactions for the development of new vaccines, diagnostic kits, and other treatments based on the targeting of SARS-CoV-2 spike protein.
    MeSH term(s) Angiotensin-Converting Enzyme 2/chemistry ; Antibodies, Neutralizing/chemistry ; COVID-19/virology ; Humans ; Models, Molecular ; Protein Binding ; Protein Interaction Domains and Motifs ; Receptors, Coronavirus/chemistry ; SARS-CoV-2/chemistry ; Spike Glycoprotein, Coronavirus/chemistry
    Chemical Substances Antibodies, Neutralizing ; Receptors, Coronavirus ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
    Keywords covid19
    Language English
    Publishing date 2020-07-04
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1358415-7
    ISSN 1420-9071 ; 1420-682X
    ISSN (online) 1420-9071
    ISSN 1420-682X
    DOI 10.1007/s00018-020-03580-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Nucleotide substitutions at the p.Gly117 and p.Thr180 mutational hot-spots of SKI alter molecular dynamics and may affect cell cycle.

    Fusco, Carmela / Nardella, Grazia / Morlino, Silvia / Micale, Lucia / Tragni, Vincenzo / Agolini, Emanuele / Novelli, Antonio / Massuras, Stefania / Giambra, Vincenzo / Pierri, Ciro Leonardo / Castori, Marco

    Journal of human genetics

    2023  Volume 69, Issue 1, Page(s) 53–58

    Abstract: Heterozygous deleterious variants in SKI cause Shprintzen-Goldberg Syndrome, which is mainly characterized by craniofacial features, neurodevelopmental disorder and thoracic aorta dilatations/aneurysms. The encoded protein is a member of the transforming ...

    Abstract Heterozygous deleterious variants in SKI cause Shprintzen-Goldberg Syndrome, which is mainly characterized by craniofacial features, neurodevelopmental disorder and thoracic aorta dilatations/aneurysms. The encoded protein is a member of the transforming growth factor beta signaling. Paucity of reported studies exploring the SGS molecular pathogenesis hampers disease recognition and clinical interpretation of private variants. Here, the unpublished c.349G>A, p.[Gly117Ser] and the recurrent c.539C>T, p.[Thr180Met] SKI variants were studied combining in silico and in vitro approach. 3D comparative modeling and calculation of the interaction energy predicted that both variants alter the SKI tertiary protein structure and its interactions. Computational data were functionally corroborated by the demonstration of an increase of MAPK phosphorylation levels and alteration of cell cycle in cells expressing the mutant SKI. Our findings confirmed the effects of SKI variants on MAPK and opened the path to study the role of perturbations of the cell cycle in SGS.
    MeSH term(s) Humans ; Molecular Dynamics Simulation ; DNA-Binding Proteins/metabolism ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Marfan Syndrome ; Cell Cycle/genetics ; Transforming Growth Factor beta
    Chemical Substances DNA-Binding Proteins ; Proto-Oncogene Proteins ; Transforming Growth Factor beta
    Language English
    Publishing date 2023-09-12
    Publishing country England
    Document type Journal Article
    ZDB-ID 1425192-9
    ISSN 1435-232X ; 1434-5161
    ISSN (online) 1435-232X
    ISSN 1434-5161
    DOI 10.1038/s10038-023-01193-7
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  8. Article ; Online: Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming.

    Palmieri, Erika M / Holewinski, Ronald / McGinity, Christopher L / Pierri, Ciro L / Maio, Nunziata / Weiss, Jonathan M / Tragni, Vincenzo / Miranda, Katrina M / Rouault, Tracey A / Andresson, Thorkell / Wink, David A / McVicar, Daniel W

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 5114

    Abstract: M1 macrophages enter a glycolytic state when endogenous nitric oxide (NO) reprograms mitochondrial metabolism by limiting aconitase 2 and pyruvate dehydrogenase (PDH) activity. Here, we provide evidence that NO targets the PDH complex by using lipoate to ...

    Abstract M1 macrophages enter a glycolytic state when endogenous nitric oxide (NO) reprograms mitochondrial metabolism by limiting aconitase 2 and pyruvate dehydrogenase (PDH) activity. Here, we provide evidence that NO targets the PDH complex by using lipoate to generate nitroxyl (HNO). PDH E2-associated lipoate is modified in NO-rich macrophages while the PDH E3 enzyme, also known as dihydrolipoamide dehydrogenase (DLD), is irreversibly inhibited. Mechanistically, we show that lipoate facilitates NO-mediated production of HNO, which interacts with thiols forming irreversible modifications including sulfinamide. In addition, we reveal a macrophage signature of proteins with reduction-resistant modifications, including in DLD, and identify potential HNO targets. Consistently, DLD enzyme is modified in an HNO-dependent manner at Cys
    MeSH term(s) Nitrogen Oxides ; Nitric Oxide ; Macrophages ; Pyruvate Dehydrogenase Complex ; Oxidoreductases ; Pyruvates
    Chemical Substances nitroxyl (GFQ4MMS07W) ; Nitrogen Oxides ; Nitric Oxide (31C4KY9ESH) ; Pyruvate Dehydrogenase Complex ; Oxidoreductases (EC 1.-) ; Pyruvates
    Language English
    Publishing date 2023-08-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-40738-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Deconstructing SARS-CoV-2 neutralization: A modular molecular framework for computational design and comparison of antibodies and nanobodies targeting the spike RBD.

    Tragni, Vincenzo / Mercurio, Ivan / Paoletti, Diletta Pia / Onofrio, Angelo / Laera, Luna / Cafferati Beltrame, Lucas / Sgobba, Maria Noemi / Guerra, Lorenzo / Volpicella, Mariateresa / De Grassi, Anna / Elia, Gabriella / Pierri, Ciro Leonardo

    Journal of medical virology

    2023  Volume 95, Issue 6, Page(s) e28875

    Abstract: Since 2020 the COVID-19 pandemic has led scientists to search for strategies to predict the transmissibility and virulence of new severe acute respiratory syndrome coronavirus 2 variants based on the estimation of the affinity of the spike receptor ... ...

    Abstract Since 2020 the COVID-19 pandemic has led scientists to search for strategies to predict the transmissibility and virulence of new severe acute respiratory syndrome coronavirus 2 variants based on the estimation of the affinity of the spike receptor binding domain (RBD) for the human angiotensin-converting enzyme 2 (ACE2) receptor and/or neutralizing antibodies. In this context, our lab developed a computational pipeline to quickly quantify the free energy of interaction at the spike RBD/ACE2 protein-protein interface, reflecting the incidence trend observed in the transmissibility/virulence of the investigated variants. In this new study, we used our pipeline to estimate the free energy of interaction between the RBD from 10 variants, and 14 antibodies (ab), or 5 nanobodies (nb), highlighting the RBD regions preferentially targeted by the investigated ab/nb. Our structural comparative analysis and interaction energy calculations allowed us to propose the most promising RBD regions to be targeted by future ab/nb to be designed by site-directed mutagenesis of existing high-affinity ab/nb, to increase their affinity for the target RBD region, for preventing spike-RBD/ACE2 interactions and virus entry in host cells. Furthermore, we evaluated the ability of the investigated ab/nb to simultaneously interact with the three RBD located on the surface of the trimeric spike protein, which can alternatively be in up- or down- (all-3-up-, all-3-down-, 1-up-/2-down-, 2-up-/1-down-) conformations.
    MeSH term(s) Humans ; SARS-CoV-2/genetics ; Angiotensin-Converting Enzyme 2 ; Single-Domain Antibodies/genetics ; COVID-19 ; Pandemics ; Antibodies, Neutralizing ; Spike Glycoprotein, Coronavirus/genetics ; Protein Binding
    Chemical Substances Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Single-Domain Antibodies ; Antibodies, Neutralizing ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
    Language English
    Publishing date 2023-06-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 752392-0
    ISSN 1096-9071 ; 0146-6615
    ISSN (online) 1096-9071
    ISSN 0146-6615
    DOI 10.1002/jmv.28875
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  10. Article: Zoledronic Acid as a Novel Dual Blocker of KIR6.1/2-SUR2 Subunits of ATP-Sensitive K

    Maqoud, Fatima / Scala, Rosa / Tragni, Vincenzo / Pierri, Ciro Leonardo / Perrone, Maria Grazia / Scilimati, Antonio / Tricarico, Domenico

    Pharmaceutics

    2021  Volume 13, Issue 9

    Abstract: Zoledronic acid (ZOL) is used as a bone-specific antiresorptive drug with antimyeloma effects. Adverse drug reactions (A.D.R.) are associated with ZOL-therapy, whose mechanics are unknown. ZOL is a nitrogen-containing molecule whose structure shows ... ...

    Abstract Zoledronic acid (ZOL) is used as a bone-specific antiresorptive drug with antimyeloma effects. Adverse drug reactions (A.D.R.) are associated with ZOL-therapy, whose mechanics are unknown. ZOL is a nitrogen-containing molecule whose structure shows similarities with nucleotides, ligands of ATP-sensitive K
    Language English
    Publishing date 2021-08-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527217-2
    ISSN 1999-4923
    ISSN 1999-4923
    DOI 10.3390/pharmaceutics13091350
    Database MEDical Literature Analysis and Retrieval System OnLINE

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