Journal: ACS Infectious Diseases

Abbreviation

ACS Infect Dis

Publisher

American Chemical Society

Journal Volumes

ISSN

2373-8227

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2015 - 201962020 - 20233
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Publications 1 - 9 of 9
  • Reduction of Influenza Virus Envelope's Fusogenicity by Viral Fusion Inhibitors
    Item type: Journal Article
    Rowse, Michael; Qiu, Shihong; Tsao, Jun; et al. (2016)
    ACS Infectious Diseases
  • Modification at the 2′-Position of the 4,5-Series of 2-Deoxystreptamine Aminoglycoside Antibiotics To Resist Aminoglycoside Modifying Enzymes and Increase Ribosomal Target Selectivity
    Item type: Journal Article
    Sati, Girish C.; Sarpe, Vikram A.; Furukawa, Takayuki; et al. (2019)
    ACS Infectious Diseases
    A series of derivatives of the 4,5-disubstituted class of 2-deoxystreptamine aminoglycoside antibiotics neomycin, paromomycin, and ribostamycin was prepared and assayed for (i) their ability to inhibit protein synthesis by bacterial ribosomes and by engineered bacterial ribosomes carrying eukaryotic decoding A sites, (ii) antibacterial activity against wild type Gram negative and positive pathogens, and (iii) overcoming resistance due to the presence of aminoacyl transferases acting at the 2′-position. The presence of five suitably positioned residual basic amino groups was found to be necessary for activity to be retained upon removal or alkylation of the 2′-position amine. As alkylation of the 2′-amino group overcomes the action of resistance determinants acting at that position and in addition results in increased selectivity for the prokaryotic over eukaryotic ribosomes, it constitutes an attractive modification for introduction into next generation aminoglycosides. In the neomycin series, the installation of small (formamide) or basic (glycinamide) amido groups on the 2′-amino group is tolerated.
  • Evaluation of Human Liver Microtissues for Drug Screening on Schistosoma mansoni Schistosomula
    Item type: Journal Article
    Lombardo, Flavio C.; Ravaynia, Paolo S.; Modena, Mario M.; et al. (2021)
    ACS Infectious Diseases
    Schistosomiasis is a major neglected tropical disease with more than 200 million infections annually. Despite only one drug, praziquantel, being available, the drug pipeline against schistosomiasis is empty, and drug screening tools have limitations. We evaluated the potential of human liver microtissues (hLiMTs) in antischistosomal drug discovery. Because hLiMTs express all human P450 enzymes, they are an excellent tool to evaluate compounds’ bioinactivation, bioactivation, and toxicity. To validate the metabolic conversion capacity of hLiMTs, we first quantified (R)- and (S)-praziquantel and the main metabolite trans-OH-praziquantel following incubation with 0.032–50 μM (0.01–15.62 μg/mL) praziquantel for up to 72 h by a validated LC-MS/MS method. We cocultured hLiMTs with newly transformed schistosomula (NTS) and evaluated the antischistosomal activity and cytotoxicity of three prodrugs terfenadine, tamoxifen citrate, and flutamide. HLiMTs converted 300–350 ng (R)-praziquantel within 24 h into trans-OH-praziquantel. We observed changes in the IC50 values for terfenadine, flutamide, and tamoxifen citrate in comparison to the standard NTS assay in vitro. Cytotoxicity was observed at high concentrations of flutamide and tamoxifen citrate. An in vitro platform containing hLiMTs could serve as an advanced drug screening tool for Schistosoma mansoni, providing information on reduced or increased activity and toxicity.
  • Cell Cycle-Dependent Kinase Cdk9 Is a Postexposure Drug Target against Human Adenoviruses
    Item type: Journal Article
    Prasad, Vibhu; Suomalainen, Maarit; Hemmi, Silvio; et al. (2017)
    ACS Infectious Diseases
  • Synthesis of Gentamicins C1, C2, and C2a and Antiribosomal and Antibacterial Activity of Gentamicins B1, C1, C1a, C2, C2a, C2b, and X2
    Item type: Journal Article
    Jana, Santanu; Rajasekaran, Parasuraman; Haldimann, Klara; et al. (2023)
    ACS Infectious Diseases
    Complementing our earlier syntheses of the gentamicins B1, C1a, C2b, and X2, we describe the synthesis of gentamicins C1, C2, and C2a characterized by methyl substitution at the 6′-position, and so present an alternative access to previous chromatographic methods for accessing these sought-after compounds. We describe the antiribosomal activity of our full set of synthetic gentamicin congeners against bacterial ribosomes and hybrid ribosomes carrying the decoding A site of the human mitochondrial, A1555G mutant mitochondrial, and cytoplasmic ribosomes and establish structure–activity relationships with the substitution pattern around ring I to antiribosomal activity, antibacterial resistance due to the presence of aminoglycoside acetyl transferases acting on the 6′-position in ring I, and literature cochlear toxicity data.
  • Synthesis and Antibacterial Activity of Propylamycin Derivatives Functionalized at the 5 ''- and Other Positions with a View to Overcoming Resistance Due to Aminoglycoside Modifying Enzymes
    Item type: Journal Article
    Lubriks, Dimitrijs; Zogota, Rimants; Sarpe, Vikram A.; et al. (2021)
    ACS Infectious Diseases
    Propylamycin (4'-deoxy-4'-propylparomomycin) is a next generation amino-glycoside antibiotic that displays increased antibacterial potency over the parent, coupled with reduced susceptibility to resistance determinants and reduced ototoxicity in the guinea pig model. Propylamycin nevertheless is inactivated by APH(3')-Ia, a specific aminoglycoside phosphotransferase isozyme that acts on the primary hydroxy group of the ribofuranosyl moiety (at the 5 ''-position). To overcome this problem, we have prepared and studied the antibacterial and antiribosomal activity of various propylamycin derivatives carrying amino or substituted amino groups at the 5 ''-position in place of the vulnerable hydroxy group. We find that the introduction of an additional basic amino group at this position, while overcoming the action of the aminoglycoside phosphoryltransferase isozymes acting at the 5 ''-position as anticipated, results in a significant drop in selectivity for the bacterial over the eukaryotic ribosomes that is predictive of increased ototoxicity. In contrast, 5 ''-deoxy-5 ''-formamidopropylamycin retains the excellent across-the-board levels of antibacterial activity of propylamycin itself, while circumventing the action of the offending aminoglycoside phosphotransferase isozymes and affording even greater selectivity for the bacterial over the eukaryotic ribosomes. Other modifications to address the susceptibility of propylamycin to the APH(3')-Ia isozyme including deoxygenation at the 3'-position and incorporation of a 6',5 ''-bis(hydroxyethylamino) modification offer no particular advantage.
  • N6 ', N6 ''', and 04 ' Modifications to Neomycin Affect Ribosomal Selectivity without Compromising Antibacterial Activity
    Item type: Journal Article
    Sati, Girish C.; Shcherbakov, Dimitri; Hobbie, Sven N.; et al. (2017)
    ACS Infectious Diseases
Publications 1 - 9 of 9