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  1. Article ; Online: Therapeutic Targeting of Pancreatic Cancer via EphA2 Dimeric Agonistic Agents

    Ahmed F. Salem / Luca Gambini / Parima Udompholkul / Carlo Baggio / Maurizio Pellecchia

    Pharmaceuticals, Vol 13, Iss 90, p

    2020  Volume 90

    Abstract: Recently, we reported on potent EphA2 targeting compounds and demonstrated that dimeric versions of such agents can exhibit remarkably increased agonistic activity in cellular assays compared to the monomers. Here we further characterize the activity of ... ...

    Abstract Recently, we reported on potent EphA2 targeting compounds and demonstrated that dimeric versions of such agents can exhibit remarkably increased agonistic activity in cellular assays compared to the monomers. Here we further characterize the activity of dimeric compounds at the structural, biochemical, and cellular level. In particular, we propose a structural model for the mechanism of receptor activation by dimeric agents and characterize the effect of most potent compounds in inducing EphA2 activation and degradation in a pancreatic cancer cell line. These cellular studies indicate that the pro-migratory effects induced by the receptor can be reversed in EphA2 knockout cells, by treatment with either a dimeric natural ligand (ephrinA1-Fc), or by our synthetic agonistic dimers. Based on these data we conclude that the proposed agents hold great potential as possible therapeutics in combination with standard of care, where these could help suppressing a major driver for cell migration and tumor metastases. Finally, we also found that, similar to ephrinA1-Fc, dimeric agents cause a sustained internalization of the EphA2 receptor, hence, with proper derivatizations, these could also be used to deliver chemotherapy selectively to pancreatic tumors.
    Keywords EphA2 ; agonistic EphA2 peptides ; 135H12 ; cell migration ; pancreatic cancer ; drug discovery ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
    Subject code 500
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Effective Tumor Targeting by EphA2-Agonist-Biotin-Streptavidin Conjugates

    Parima Udompholkul / Carlo Baggio / Luca Gambini / Yu Sun / Ming Zhao / Robert M. Hoffman / Maurizio Pellecchia

    Molecules, Vol 26, Iss 3687, p

    2021  Volume 3687

    Abstract: We recently reported on a potent synthetic agent, 135H11, that selectively targets the receptor tyrosine kinase, EphA2. While 135H11 possesses a relatively high binding affinity for the ligand-binding domain of EphA2 (Kd~130 nM), receptor activation in ... ...

    Abstract We recently reported on a potent synthetic agent, 135H11, that selectively targets the receptor tyrosine kinase, EphA2. While 135H11 possesses a relatively high binding affinity for the ligand-binding domain of EphA2 (Kd~130 nM), receptor activation in the cell required the synthesis of dimeric versions of such agent (namely 135H12). This was expected given that the natural ephrin ligands also need to be dimerized or clustered to elicit agonistic activity in cell. In the present report we investigated whether the agonistic activity of 135H11 could be enhanced by biotin conjugation followed by complex formation with streptavidin. Therefore, we measured the agonistic EphA2 activity of 135H11-biotin (147B5) at various agent/streptavidin ratios, side by side with 135H12, and a scrambled version of 147B5 in pancreatic- and breast-cancer cell lines. The (147B5) n -streptavidin complexes (when n = 2, 3, 4, but not when n = 1) induced a strong receptor degradation effect in both cell lines compared to 135H12 or the (scrambled-147B5) 4 -streptavidin complex as a control, indicating that multimerization of the targeting agent resulted in an increased ability to cause receptor clustering and internalization. Subsequently, we prepared an Alexa-Fluor-streptavidin conjugate to demonstrate that (147B5) 4 -AF-streptavidin, but not the scrambled equivalent complex, concentrates in pancreatic and breast cancers in orthotopic nude-mouse models. Hence, we conclude that these novel targeting agents, with proper derivatization with imaging reagents or chemotherapy, can be used as diagnostics, and/or to deliver chemotherapy selectively to EphA2-expressing tumors.
    Keywords agonistic EphA2 peptides ; streptavidin ; pancreatic cancer ; breast cancer ; cancer imaging ; orthotopic cancer models ; Organic chemistry ; QD241-441
    Subject code 616
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Book ; Online: Potential Therapeutic Targeting of Coronavirus Spike Glycoprotein Priming

    Elisa Barile / Carlo Baggio / Luca Gambini / Sergey A. Shiryaev / Alex Y. Strongin and Maurizio Pellecchia

    Molecules ; Volume 25 ; Issue 10

    2020  

    Abstract: Processing of certain viral proteins and bacterial toxins by host serine proteases is a frequent and critical step in virulence. The coronavirus spike glycoprotein contains three (S1, S2, and S2′ ... cleavage sites that are processed by human host ... ...

    Abstract Processing of certain viral proteins and bacterial toxins by host serine proteases is a frequent and critical step in virulence. The coronavirus spike glycoprotein contains three (S1, S2, and S2′

    ) cleavage sites that are processed by human host proteases. The exact nature of these cleavage sites, and their respective processing proteases, can determine whether the virus can cross species and the level of pathogenicity. Recent comparisons of the genomes of the highly pathogenic SARS-CoV2 and MERS-CoV, with less pathogenic strains (e.g., Bat-RaTG13, the bat homologue of SARS-CoV2) identified possible mutations in the receptor binding domain and in the S1 and S2′

    cleavage sites of their spike glycoprotein. However, there remains some confusion on the relative roles of the possible serine proteases involved for priming. Using anthrax toxin as a model system, we show that in vivo inhibition of priming by pan-active serine protease inhibitors can be effective at suppressing toxicity. Hence, our studies should encourage further efforts in developing either pan-serine protease inhibitors or inhibitor cocktails to target SARS-CoV2 and potentially ward off future pandemics that could develop because of additional mutations in the S-protein priming sequence in coronaviruses.
    Keywords COVID19 ; SARS-COV2 ; Anthrax toxin ; protecting antigen ; furin ; TMPRSS2 ; covid19
    Subject code 570
    Language English
    Publishing date 2020-05-22
    Publisher Multidisciplinary Digital Publishing Institute
    Publishing country ch
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Potential Therapeutic Targeting of Coronavirus Spike Glycoprotein Priming

    Elisa Barile / Carlo Baggio / Luca Gambini / Sergey A. Shiryaev / Alex Y. Strongin and Maurizio Pellecchia

    Molecules, Vol 25, Iss 2424, p

    2020  Volume 2424

    Abstract: Processing of certain viral proteins and bacterial toxins by host serine proteases is a frequent and critical step in virulence. The coronavirus spike glycoprotein contains three (S1, S2, and S2′) cleavage sites that are processed by human host proteases. ...

    Abstract Processing of certain viral proteins and bacterial toxins by host serine proteases is a frequent and critical step in virulence. The coronavirus spike glycoprotein contains three (S1, S2, and S2′) cleavage sites that are processed by human host proteases. The exact nature of these cleavage sites, and their respective processing proteases, can determine whether the virus can cross species and the level of pathogenicity. Recent comparisons of the genomes of the highly pathogenic SARS-CoV2 and MERS-CoV, with less pathogenic strains (e.g., Bat-RaTG13, the bat homologue of SARS-CoV2) identified possible mutations in the receptor binding domain and in the S1 and S2′ cleavage sites of their spike glycoprotein. However, there remains some confusion on the relative roles of the possible serine proteases involved for priming. Using anthrax toxin as a model system, we show that in vivo inhibition of priming by pan-active serine protease inhibitors can be effective at suppressing toxicity. Hence, our studies should encourage further efforts in developing either pan-serine protease inhibitors or inhibitor cocktails to target SARS-CoV2 and potentially ward off future pandemics that could develop because of additional mutations in the S-protein priming sequence in coronaviruses.
    Keywords COVID19 ; SARS-COV2 ; Anthrax toxin ; protecting antigen ; furin ; TMPRSS2 ; Organic chemistry ; QD241-441 ; covid19
    Subject code 570
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

  5. Article ; Online: Correction

    Luca Gambini / Luca Rizzi / Alessandro Pedretti / Orazio Taglialatela-Scafati / Mario Carucci / Andrea Pancotti / Corinna Galli / Martin Read / Emanuele Giurisato / Sergio Romeo / Ilaria Russo

    PLoS ONE, Vol 11, Iss 1, p e

    Picomolar Inhibition of Plasmepsin V, an Essential Malaria Protease, Achieved Exploiting the Prime Region.

    2016  Volume 0146627

    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2016-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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  6. Article ; Online: Picomolar Inhibition of Plasmepsin V, an Essential Malaria Protease, Achieved Exploiting the Prime Region.

    Luca Gambini / Luca Rizzi / Alessandro Pedretti / Orazio Taglialatela-Scafati / Mario Carucci / Andrea Pancotti / Corinna Galli / Martin Read / Emanuele Giurisato / Sergio Romeo / Ilaria Russo

    PLoS ONE, Vol 10, Iss 11, p e

    2015  Volume 0142509

    Abstract: Malaria is an infectious disease caused by Plasmodium parasites. It results in an annual death-toll of ~ 600,000. Resistance to all medications currently in use exists, and novel antimalarial drugs are urgently needed. Plasmepsin V (PmV) is an essential ... ...

    Abstract Malaria is an infectious disease caused by Plasmodium parasites. It results in an annual death-toll of ~ 600,000. Resistance to all medications currently in use exists, and novel antimalarial drugs are urgently needed. Plasmepsin V (PmV) is an essential Plasmodium protease and a highly promising antimalarial target, which still lacks molecular characterization and drug-like inhibitors. PmV, cleaving the PExEl motif, is the key enzyme for PExEl-secretion, an indispensable parasitic process for virulence and infection. Here, we describe the accessibility of PmV catalytic pockets to inhibitors and propose a novel strategy for PmV inhibition. We also provide molecular and structural data suitable for future drug development. Using high-throughput platforms, we identified a novel scaffold that interferes with PmV in-vitro at picomolar ranges (~ 1,000-fold more active than available compounds). Via systematic replacement of P and P' regions, we assayed the physico-chemical requirements for PmV inhibition, achieving an unprecedented IC50 of ~20 pM. The hydroxyethylamine moiety, the hydrogen acceptor group in P2', the lipophilic groups upstream to P3, the arginine and other possible substitutions in position P3 proved to be critically important elements in achieving potent inhibition. In-silico analyses provided essential QSAR information and model validation. Our inhibitors act 'on-target', confirmed by cellular interference of PmV function and biochemical interaction with inhibitors. Our inhibitors are poorly performing against parasite growth, possibly due to poor stability of their peptidic component and trans-membrane permeability. The lowest IC50 for parasite growth inhibition was ~ 15 μM. Analysis of inhibitor internalization revealed important pharmacokinetic features for PExEl-based molecules. Our work disclosed novel pursuable drug design strategies for highly efficient PmV inhibition highlighting novel molecular elements necessary for picomolar activity against PmV. All the presented data are discussed in ...
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2015-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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