Publications by authors named "Davide Deodato"

18 Publications

  • Page 1 of 1

Photoactivatable AMPA for the study of glutamatergic neuronal transmission using two-photon excitation.

Org Biomol Chem 2021 Jun;19(25):5589-5594

New York University Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates. and Department of Chemistry, University of Georgia, Athens, GA 30602, USA.

We report a photoactivatable agonist of the AMPA subtype of ionotropic glutamate receptors, TMP-CyHQ-AMPA, which was designed to study the fast excitatory transmission between neurons. Upon visible light excitation, TMP-CyHQ-AMPA quantitatively released AMPA in high quantum yield on an ultra-short timescale. Intriguingly, the photolyisis can be carried out using 2-photon excitation (2PE) with remarkable efficiency, giving a two-photon uncaging action cross section (δu) value of 1.71 GM. TMP-CyHQ-AMPA is soluble in pysiological buffer and no hydrolysis was detected in the absence of light. Molecular docking experiments indicated that the photocaging strategy abolishes the affinity of AMPA for the GluR2 receptor and no GABAergic effects (as commonly observed in caged glutamates) are expected. TMP-CyHQ-AMPA can be used to study glutamatergic neuronal transmission with exceptional spatial-temporal resolution in complex tissue preparations.
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http://dx.doi.org/10.1039/d1ob01006aDOI Listing
June 2021

Practical Synthesis of Quinoline-Protected Morpholino Oligomers for Light-Triggered Regulation of Gene Function.

Molecules 2020 Apr 29;25(9). Epub 2020 Apr 29.

New York University Abu Dhabi, PO Box 129188, Abu Dhabi, UAE.

Photoactivatable cyclic caged morpholino oligomers (ccMOs) represent a promising tool to selectively regulate gene expression with spatiotemporal control. Nevertheless, some challenges associated with the preparation of these reagents have limited their broader use in biological settings. We describe a novel ccMO design that overcomes many of the challenges and considerably expedites the synthetic preparation. The key factor is the introduction of an ethynyl function on the photocleavable linker to facilitate the use of a Huisgen 1,3-dipolar cycloaddition for the coupling reaction with the oligonucleotide. Compared to previous strategies, this modification reduces the number of synthetic steps and significantly improves the total yield and the stability of the linker. We used the alkynyl-functionalized linker for the preparation of two different ccMOs targeting the mRNA of the glutamic acid decarboxylase genes, and . HPLC analysis confirms that the caging strategy successfully inhibits the DNA binding ability, and the activity can be restored by brief illumination with 405-nm light. Overall, the straightforward preparation together with the clean and fast photochemistry make these caged antisense reagents excellent tools to modulate gene function in-vivo with spatial and temporal precision.
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http://dx.doi.org/10.3390/molecules25092078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248704PMC
April 2020

Two-Photon Excitable Photoremovable Protecting Groups Based on the Quinoline Scaffold for Use in Biology.

J Org Chem 2020 01 18;85(2):726-744. Epub 2019 Dec 18.

New York University Abu Dhabi , P.O. Box 129188, Abu Dhabi , United Arab Emirates.

Photoremovable protecting groups (PPGs) are powerful tools for physiological studies, harnessing light as an on/off switch to provide tight spatio-temporal control over the release of biological effectors through two-photon excitation (2PE) in tissue culture and whole-animal studies. We carried out a series of systematic structural modifications to the (8-cyano-7-hydroxyquinolin-2-yl)methyl (CyHQ) chromophore to conduct an SAR study with the aim of enhancing its photochemical properties, especially its two-photon uncaging action cross section (δ). The best results were obtained when substituents were added at the C4 position, which improved δ for release of acetate up to 7-fold, while retaining all the other excellent properties of the CyHQ PPG, including high quantum yield (Φ), low susceptibility to spontaneous hydrolysis in the dark, and good aqueous solubility. Hammett correlation analysis suggested that photolysis efficiency is favored by electron-rich substituents at C4, giving important insights into the mechanism of the photolysis reaction. The four best CyHQ derivatives were used to mediate the efficient release of homopiperonylic acid in high yield under simulated physiological conditions. Our efforts have led to the development of 2PE-sensitive PPGs with remarkable δ values (up to 2.64 GM), excellent quantum yields (up to 0.88), and high-yielding effector release (up to 92%).
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http://dx.doi.org/10.1021/acs.joc.9b02780DOI Listing
January 2020

Photorearrangement of Quinoline-Protected Dialkylanilines and the Photorelease of Aniline-Containing Biological Effectors.

J Org Chem 2019 06 28;84(11):7342-7353. Epub 2019 May 28.

New York University Abu Dhabi , P.O. Box 129188, Abu Dhabi , United Arab Emirates.

The direct release of dialkylanilines was achieved by controlling the outcome of a photorearrangement reaction promoted by the (8-cyano-7-hydroxyquinolin-2-yl)methyl (CyHQ) photoremovable protecting group. The substrate scope was investigated to obtain structure-activity relationships and to propose a reaction mechanism. Introducing a methyl substituent at the 2-methyl position of the CyHQ core enabled the bypass of the photorearrangement and significantly improved the aniline release efficiency. We successfully applied the strategy to the photoactivation of mifepristone (RU-486), an antiprogestin drug that is also used to induce the LexPR gene expression system in zebrafish and the gene-switch regulatory system based on the pGL-VP chimeric regulator in mammals.
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http://dx.doi.org/10.1021/acs.joc.9b01031DOI Listing
June 2019

Alkyl-guanidine Compounds as Potent Broad-Spectrum Antibacterial Agents: Chemical Library Extension and Biological Characterization.

J Med Chem 2018 10 11;61(20):9162-9176. Epub 2018 Oct 11.

Department of Biotechnology, Chemistry, and Pharmacy , University of Siena , I-53100 Siena , Italy.

Nowadays, the increasing of multidrug-resistant pathogenic bacteria represents a serious threat to public health, and the lack of new antibiotics is becoming a global emergency. Therefore, research in antibacterial fields is urgently needed to expand the currently available arsenal of drugs. We have recently reported an alkyl-guanidine derivative (2), characterized by a symmetrical dimeric structure, as a good candidate for further developments, with a high antibacterial activity against both Gram-positive and Gram-negative strains. In this study, starting from its chemical scaffold, we synthesized a small library of analogues. Moreover, biological and in vitro pharmacokinetic characterizations were conducted on some selected derivatives, revealing notable properties: broad-spectrum profile, activity against resistant clinical isolates, and appreciable aqueous solubility. Interestingly, 2 seems neither to select for resistant strains nor to macroscopically alter the membranes, but further studies are required to determine the mode of action.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00619DOI Listing
October 2018

Bypassing Glutamic Acid Decarboxylase 1 (Gad1) Induced Craniofacial Defects with a Photoactivatable Translation Blocker Morpholino.

ACS Chem Neurosci 2019 01 24;10(1):266-278. Epub 2018 Sep 24.

New York University Abu Dhabi , PO Box 129188, Abu Dhabi , United Arab Emirates.

γ-Amino butyric acid (GABA) mediated signaling is critical in the central and enteric nervous systems, pancreas, lungs, and other tissues. It is associated with many neurological disorders and craniofacial development. Glutamic acid decarboxylase (GAD) synthesizes GABA from glutamate, and knockdown of the gad1 gene results in craniofacial defects that are lethal in zebrafish. To bypass this and enable observation of the neurological defects resulting from knocking down gad1 expression, a photoactivatable morpholino oligonucleotide (MO) against gad1 was prepared by cyclization with a photocleavable linker rendering the MO inactive. The cyclized MO was stable in the dark and toward degradative enzymes and was completely linearized upon brief exposure to 405 nm light. In the course of investigating the function of the ccMOs in zebrafish, we discovered that zebrafish possess paralogous gad1 genes, gad1a and gad1b. A gad1b MO injected at the 1-4 cell stage caused severe morphological defects in head development, which could be bypassed, enabling the fish to develop normally, if the fish were injected with a photoactivatable, cyclized gad1b MO and grown in the dark. At 1 day post fertilization (dpf), light activation of the gad1b MO followed by observation at 3 and 7 dpf led to increased and abnormal electrophysiological brain activity compared to wild type animals. The photocleavable linker can be used to cyclize and inactivate any MO, and represents a general strategy to parse the function of developmentally important genes in a spatiotemporal manner.
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http://dx.doi.org/10.1021/acschemneuro.8b00231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337688PMC
January 2019

Synthesis and biological evaluation of a library of hybrid derivatives as inhibitors of influenza virus PA-PB1 interaction.

Eur J Med Chem 2018 Sep 13;157:743-758. Epub 2018 Aug 13.

Dipartimento di Biotecnologie, Chimica e Farmacia, Università; Degli Studi di Siena, Via A. Moro, I-53100 Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, United States; Lead Discovery Siena S.r.l., Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy.

The limited treatment options against influenza virus along with the growing public health concerns regarding the continuous emergence of drug-resistant viruses make essential the development of new anti-flu agents with novel mechanisms of action. One of the most attractive targets is the interaction between two subunits of the RNA-dependent RNA polymerase, PA and PB1. Herein we report the rational design of hybrid compounds starting from a 3-cyano-4,6-diphenylpyridine scaffold recently identified as disruptor of PA-PB1 interactions. Guided by the previously reported SAR data, a library of amino acid derivatives was synthesized. The biological evaluation led to the identification of new PA-PB1 inhibitors, that do not show appreciable toxicity. Molecular modeling shed further lights on the inhibition mechanism of these compounds.
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http://dx.doi.org/10.1016/j.ejmech.2018.08.032DOI Listing
September 2018

Design, synthesis, SAR and biological investigation of 3-(carboxymethyl)rhodanine and aminothiazole inhibitors of Mycobacterium tuberculosis Zmp1.

Bioorg Med Chem Lett 2018 02 31;28(4):637-641. Epub 2018 Jan 31.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53019 Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Bldg., Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA. Electronic address:

Sixteen 3-(carboxymethyl)rhodanines, and twelve aminothiazoles as rhodanine-mimetics were designed, synthesized and tested as inhibitors of the Zmp1 enzyme from Mycobacterium tuberculosis (Mtb). Almost all rhodanines (5a-d, 5f-n, and 7a-b) exhibited Zmp1 inhibition with IC values in the range 1.3-43.9 µM, whereas only aminothiazoles 12b and 12d proved active with IC values of 41.3 and 35.7 µM, respectively. Structure-activity relationships (SAR) were coupled with molecular modeling studies to highlight structural determinants for Zmp1 inhibition. Moreover, rhodanines 5a and 5c induced 23.4 and 53.8% of Mtb growth inhibition in THP-1 infected cells, respectively, at the non-toxic concentration of 10 µg/ml. This work represents a step forward in targeting Zmp1 by small molecules.
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http://dx.doi.org/10.1016/j.bmcl.2018.01.031DOI Listing
February 2018

Photochemical Activation of Tertiary Amines for Applications in Studying Cell Physiology.

J Am Chem Soc 2017 09 29;139(36):12591-12600. Epub 2017 Aug 29.

New York University Abu Dhabi , P.O. Box 129188, Abu Dhabi, United Arab Emirates.

Representative tertiary amines were linked to the 8-cyano-7-hydroxyquinolinyl (CyHQ) photoremovable protecting group (PPG) to create photoactivatable forms suitable for use in studying cell physiology. The photoactivation of tamoxifen and 4-hydroxytamoxifen, which can be used to activate Cre recombinase and CRISPR-Cas9 gene editing, demonstrated that highly efficient release of bioactive molecules could be achieved through one- and two-photon excitation (1PE and 2PE). CyHQ-protected anilines underwent a photoaza-Claisen rearrangement instead of releasing amines. Time-resolved spectroscopic studies revealed that photorelease of the tertiary amines was extremely fast, occurring from a singlet excited state of CyHQ on the 70 ps time scale.
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http://dx.doi.org/10.1021/jacs.7b06363DOI Listing
September 2017

Design and synthesis of a novel inhibitor of T. Viride chitinase through an in silico target fishing protocol.

Bioorg Med Chem Lett 2017 08 10;27(15):3332-3336. Epub 2017 Jun 10.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA; Lead Discovery Siena s.r.l, Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy. Electronic address:

In the last ten years, we identified and developed a new therapeutic class of antifungal agents, the macrocyclic amidinoureas. These compounds are active against several Candida species, including clinical isolates resistant to currently available antifungal drugs. The mode of action of these molecules is still unknown. In this work, we developed an in-silico target fishing procedure to identify a possible target for this class of compounds based on shape similarity, inverse docking procedure and consensus score rank-by-rank. Chitinase enzyme emerged as possible target. To confirm this hypothesis a novel macrocyclic derivative has been produced, specifically designed to increase the inhibition of the chitinase. Biological evaluation highlights a stronger enzymatic inhibition for the new derivative, while its antifungal activity drops probably because of pharmacokinetic issues. Collectively, our data suggest that chitinase represent at least one of the main target of macrocyclic amidinoureas.
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http://dx.doi.org/10.1016/j.bmcl.2017.06.016DOI Listing
August 2017

A spectroscopic study of the excited state proton transfer processes of (8-bromo-7-hydroxyquinolin-2-yl)methyl-protected phenol in aqueous solutions.

Photochem Photobiol Sci 2017 Apr;16(4):575-584

Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, People's Republic of China.

A combination of spectroscopic methods and density functional theory (DFT) computations was used to study the excited state proton transfer (ESPT) processes of (8-bromo-7-hydroxyquinolin-2-yl)methyl-protected phenol (BHQ-OPh). Characterization of the prototropic forms of BHQ-OPh in different solvent environments revealed that the neutral form predominates in acetonitrile and in 1 : 1 acetonitrile/water (pH 5.0), whereas the anionic form predominates in 1 : 1 acetonitrile/PBS (pH 7.4). Both the neutral and anionic forms were significantly populated in 1 : 1 acetonitrile/water. Upon irradiation in acetonitrile the triplet neutral form was observed, whereas the triplet anionic form was detected in 1 : 1 acetonitrile/PBS (pH 7.4). The existence of the triplet tautomeric form of BHQ-OPh in both 1 : 1 acetonitrile/water and 1 : 1 acetonitrile/water (pH 5.0), and the ESPT processes from the neutral to the anionic to the tautomeric forms in the excited state were observed using time-resolved spectroscopy. A reaction mechanism in 1 : 1 acetonitrile/water and 1 : 1 acetonitrile/water (pH 5.0) was proposed based on the spectroscopic and DFT computational results. A comparison of the results for BHQ-OPh with those of BHQ-OAc reveals that the initial prototropic states and photochemical processes are similar. The understanding gained of the initial photo-induced processes of BHQ-based photoremovable protecting groups (PPGs) is useful for the design of new quinolinyl-based PPGs for specialized applications.
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http://dx.doi.org/10.1039/c6pp00377jDOI Listing
April 2017

Biological Characterization and in Vivo Assessment of the Activity of a New Synthetic Macrocyclic Antifungal Compound.

J Med Chem 2016 04 19;59(8):3854-66. Epub 2016 Apr 19.

Department of Biotechnology Chemistry and Pharmacy, University of Siena , I-53100 Siena, Italy.

We recently identified a novel family of macrocyclic amidinoureas showing potent antifungal activity against Candida spp. In this study, we demonstrate the fungicidal effect of these compounds as well as their killing activity in a dose-dependent manner. Transcriptional analysis data indicate that our molecules induce a significant change in the transcriptome involving ATP binding cassette (ABC) transporter genes. Notably, experiments against Candida albicans mutants lacking those genes showed resistance to the compound, suggesting the involvement of ABC transporters in the uptake or intracellular accumulation of the molecule. To probe the mode of action, we performed fluorescence microscopy experiments on fungal cells treated with an ad-hoc synthesized fluorescent derivative. Fluorescence microscopy images confirm the ability of the compound to cross the membrane and show a consistent accumulation within the cytoplasm. Finally, we provide data supporting the in vivo efficacy in a systemic infection murine model setup with a drug-resistant strain of C. albicans.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00018DOI Listing
April 2016

4,6-Diphenylpyridines as Promising Novel Anti-Influenza Agents Targeting the PA-PB1 Protein-Protein Interaction: Structure-Activity Relationships Exploration with the Aid of Molecular Modeling.

J Med Chem 2016 Mar 11;59(6):2688-703. Epub 2016 Mar 11.

Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via A. Moro, I-53100 Siena, Italy.

Influenza is an infectious disease that represents an important public health burden, with high impact on the global morbidity, mortality, and economy. The poor protection and the need of annual updating of the anti-influenza vaccine, added to the rapid emergence of viral strains resistant to current therapy make the need for antiviral drugs with novel mechanisms of action compelling. In this regard, the viral RNA polymerase is an attractive target that allows the design of selective compounds with reduced risk of resistance. In previous studies we showed that the inhibition of the polymerase acidic protein-basic protein 1 (PA-PB1) interaction is a promising strategy for the development of anti-influenza agents. Starting from the previously identified 3-cyano-4,6-diphenyl-pyridines, we chemically modified this scaffold and explored its structure-activity relationships. Noncytotoxic compounds with both the ability of disrupting the PA-PB1 interaction and antiviral activity were identified, and their mechanism of target binding was clarified with molecular modeling simulations.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01935DOI Listing
March 2016

Development and in Vitro Evaluation of a Microbicide Gel Formulation for a Novel Non-Nucleoside Reverse Transcriptase Inhibitor Belonging to the N-Dihydroalkyloxybenzyloxopyrimidines (N-DABOs) Family.

J Med Chem 2016 Mar 8;59(6):2747-59. Epub 2016 Mar 8.

Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via A. De Gasperi 2, I-53100 Siena, Italy.

Preventing HIV transmission by the use of a vaginal microbicide is a topic of considerable interest in the fight against AIDS. Both a potent anti-HIV agent and an efficient formulation are required to develop a successful microbicide. In this regard, molecules able to inhibit the HIV replication before the integration of the viral DNA into the genetic material of the host cells, such as entry inhibitors or reverse transcriptase inhibitors (RTIs), are ideal candidates for prevention purpose. Among RTIs, S- and N-dihydroalkyloxybenzyloxopyrimidines (S-DABOs and N-DABOs) are interesting compounds active at nanomolar concentration against wild type of RT and with a very interesting activity against RT mutations. Herein, novel N-DABOs were synthesized and tested as anti-HIV agents. Furthermore, their mode of binding was studied by molecular modeling. At the same time, a vaginal microbicide gel formulation was developed and tested for one of the most promising candidates.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01979DOI Listing
March 2016

Synthesis of linear and cyclic guazatine derivatives endowed with antibacterial activity.

Bioorg Med Chem Lett 2014 Dec 14;24(23):5525-9. Epub 2014 Oct 14.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA; Lead Discovery Siena s.r.l, Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy. Electronic address:

Antibiotic resistance has reached alarming levels in many clinically-relevant human pathogens, and there is an increasing clinical need for new antibiotics active on drug-resistant Gram-negative pathogens who rapidly evolve towards pandrug resistance phenotypes. Here, we report on two related classes of guanidinic compounds endowed with antibacterial activity. The two best compounds (9a and 13d) exhibited the most potent antibacterial activity with MIC values ranging 0.12-8 μg/ml with most tested pathogens, including both Gram-positive and Gram-negative bacteria. Interestingly, MIC values were not affected (1-8 μg/ml) when measured using recent clinical isolates with various antibiotic resistance determinants. The results reported herein identify guazatine derivatives as an interesting starting point for the optimization of a potentially novel class of antibacterial agents.
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http://dx.doi.org/10.1016/j.bmcl.2014.09.081DOI Listing
December 2014

Discovery of the first potent and selective Mycobacterium tuberculosis Zmp1 inhibitor.

Bioorg Med Chem Lett 2014 Jun 13;24(11):2508-11. Epub 2014 Apr 13.

Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Bldg., Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA. Electronic address:

The Mycobacterium tuberculosis extracellular zinc metalloprotease 1 (Zmp1) has been proposed to play a key role in phagosome maturation and to enhance the survival of Mycobacterium tuberculosis in the host. Consequently, small molecule inhibitors of Zmp1 are of pivotal importance as a tool to better understand the pathogenicity of Zmp1 and as lead candidates for pharmacological intervention. Here we combined in silico structure-based inhibitor design with biochemical studies to discover and characterize the first potent competitive Zmp1 inhibitor showing a Ki of 94 nM and a high selectivity for Zmp1 with respect to human Neprilysin.
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http://dx.doi.org/10.1016/j.bmcl.2014.04.004DOI Listing
June 2014

The fight against the influenza A virus H1N1: synthesis, molecular modeling, and biological evaluation of benzofurazan derivatives as viral RNA polymerase inhibitors.

ChemMedChem 2014 Jan 27;9(1):129-50. Epub 2013 Nov 27.

Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. De Gasperi 2, 53100 Siena (Italy).

The influenza RNA polymerase complex, which consists of the three subunits PA, PB1, and PB2, is a promising target for the development of new antiviral drugs. A large library of benzofurazan compounds was synthesized and assayed against influenza virus A/WSN/33 (H1N1). Most of the new derivatives were found to act by inhibiting the viral RNA polymerase complex through disruption of the complex formed between subunits PA and PB1. Docking studies were also performed to elucidate the binding mode of benzofurazans within the PB1 binding site in PA and to identify amino acids involved in their mechanism of action. The predicted binding pose is fully consistent with the biological data and lays the foundation for the rational development of more effective PA-PB1 inhibitors.
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http://dx.doi.org/10.1002/cmdc.201300378DOI Listing
January 2014

Discovery and synthesis of novel benzofurazan derivatives as inhibitors of influenza A virus.

Bioorg Med Chem Lett 2013 Oct 17;23(20):5575-7. Epub 2013 Aug 17.

PiKe Pharma GmbH, Zurich, Switzerland.

The identification of a novel hit compound inhibitor of the protein-protein interaction between the influenza RNA-polymerase PA and PB1 subunits has been accomplished by means of high-throughput screening. A small family of structurally related molecules has been synthesized and biologically evaluated with most of the compounds showing micromolar potency of inhibition against viral replication.
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http://dx.doi.org/10.1016/j.bmcl.2013.08.048DOI Listing
October 2013
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