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  • 1
    Online Resource
    Online Resource
    Discovery of Amoebicidal Compounds by Combining Computational and Experimental Approaches
    American Society for Microbiology ; 2021
    In:  Antimicrobial Agents and Chemotherapy Vol. 65, No. 2 ( 2021-01-20)
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 65, No. 2 ( 2021-01-20)
    Abstract: Pathogenic and opportunistic free-living amoebae such as Acanthamoeba spp. can cause keratitis ( Acanthamoeba keratitis [AK]), which may ultimately lead to permanent visual impairment or blindness. Acanthamoeba can also cause rare but usually fatal granulomatous amoebic encephalitis (GAE). Current therapeutic options for AK require a lengthy treatment with nonspecific drugs that are often associated with adverse effects. Recent developments in the field led us to target cAMP pathways, specifically phosphodiesterase. Guided by computational tools, we targeted the Acanthamoeba phosphodiesterase RegA. Computational studies led to the construction and validation of a homology model followed by a virtual screening protocol guided by induced-fit docking and chemical scaffold analysis using our medicinal and biological chemistry (MBC) chemical library. Subsequently, 18 virtual screening hits were prioritized for further testing in vitro against Acanthamoeba castellanii , identifying amoebicidal hits containing piperidine and urea imidazole cores. Promising activities were confirmed in the resistant cyst form of the amoeba and in additional clinical Acanthamoeba strains, increasing their therapeutic potential. Mechanism-of-action studies revealed that these compounds produce apoptosis through reactive oxygen species (ROS)-mediated mitochondrial damage. These chemical families show promise for further optimization to produce effective antiacanthamoebal drugs.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.01749-20
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2021
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    detail.hit.zdb_id: 217602-6
    SSG: 12
    SSG: 15,3
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Imidazole Derivatives as Promising Agents for the Treatment of Chagas Disease
    American Society for Microbiology ; 2019
    In:  Antimicrobial Agents and Chemotherapy Vol. 63, No. 4 ( 2019-04)
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 63, No. 4 ( 2019-04)
    Abstract: More than 100 years after being first described, Chagas disease remains endemic in 21 Latin American countries and has spread to other continents. Indeed, this disease, which is caused by the protozoan parasite Trypanosoma cruzi , is no longer just a problem for the American continents but has become a global health threat. Current therapies, i.e., nifurtimox and benznidazole (Bz), are far from being adequate, due to their undesirable effects and their lack of efficacy in the chronic phases of the disease. In this work, we present an in-depth phenotypic evaluation in T. cruzi of a new class of imidazole compounds, which were discovered in a previous phenotypic screen against different trypanosomatids and were designed as potential inhibitors of cAMP phosphodiesterases (PDEs). The confirmation of several activities similar or superior to that of Bz prompted a synthesis program of hit optimization and extended structure-activity relationship aimed at improving drug-like properties such as aqueous solubility, which resulted in additional hits with 50% inhibitory concentration (IC 50 ) values similar to that of Bz. The cellular effects of one representative hit, compound 9, on bloodstream trypomastigotes were further investigated. Transmission electron microscopy revealed cellular changes, after just 2 h of incubation with the IC 50 concentration, that were consistent with induced autophagy and osmotic stress, mechanisms previously linked to cAMP signaling. Compound 9 induced highly significant increases in both cellular and medium cAMP levels, confirming that inhibition of T. cruzi PDE(s) is part of its mechanism of action. The potent and selective activity of this imidazole-based PDE inhibitor class against T. cruzi constitutes a successful repurposing of research into inhibitors of mammalian PDEs.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.02156-18
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2019
    detail.hit.zdb_id: 1496156-8
    detail.hit.zdb_id: 217602-6
    SSG: 12
    SSG: 15,3
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Cyclic Nucleotide-Specific Phosphodiesterases as Potential Drug Targets for Anti-Leishmania Therapy
    American Society for Microbiology ; 2018
    In:  Antimicrobial Agents and Chemotherapy Vol. 62, No. 10 ( 2018-10)
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 62, No. 10 ( 2018-10)
    Abstract: The available treatments for leishmaniasis are less than optimal due to inadequate efficacy, toxic side effects, and the emergence of resistant strains, clearly endorsing the urgent need for discovery and development of novel drug candidates. Ideally, these should act via an alternative mechanism of action to avoid cross-resistance with the current drugs. As cyclic nucleotide-specific phosphodiesterases (PDEs) of Leishmania major have been postulated as putative drug targets, a series of potential inhibitors of Leishmania PDEs were explored. Several displayed potent and selective in vitro activity against L. infantum intracellular amastigotes. One imidazole derivative, compound 35, was shown to reduce the parasite loads in vivo and to increase the cellular cyclic AMP (cAMP) level at in a dose-dependent manner at just 2× and 5× the 50% inhibitory concentration (IC 50 ), indicating a correlation between antileishmanial activity and increased cellular cAMP levels. Docking studies and molecular dynamics simulations pointed to imidazole 35 exerting its activity through PDE inhibition. This study establishes for the first time that inhibition of cAMP PDEs can potentially be exploited for new antileishmanial chemotherapy.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.00603-18
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2018
    detail.hit.zdb_id: 1496156-8
    detail.hit.zdb_id: 217602-6
    SSG: 12
    SSG: 15,3
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Nucleoside Inhibitors of Tick-Borne Encephalitis Virus
    American Society for Microbiology ; 2015
    In:  Antimicrobial Agents and Chemotherapy Vol. 59, No. 9 ( 2015-09), p. 5483-5493
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 59, No. 9 ( 2015-09), p. 5483-5493
    Abstract: Tick-borne encephalitis virus (TBEV) is a leading cause of human neuroinfections in Europe and Northeast Asia. There are no antiviral therapies for treating TBEV infection. A series of nucleoside analogues was tested for the ability to inhibit the replication of TBEV in porcine kidney cells and human neuroblastoma cells. The interactions of three nucleoside analogues with viral polymerase were simulated using advanced computational methods. The nucleoside analogues 7-deaza-2′- C -methyladenosine (7-deaza-2′-CMA), 2′- C -methyladenosine (2′-CMA), and 2′-C-methylcytidine (2′-CMC) inhibited TBEV replication. These compounds showed dose-dependent inhibition of TBEV-induced cytopathic effects, TBEV replication (50% effective concentrations [EC 50 ]of 5.1 ± 0.4 μM for 7-deaza-2′-CMA, 7.1 ± 1.2 μM for 2′-CMA, and 14.2 ± 1.9 μM for 2′-CMC) and viral antigen production. Notably, 2′-CMC was relatively cytotoxic to porcine kidney cells (50% cytotoxic concentration [CC 50 ] of ∼50 μM). The anti-TBEV effect of 2′-CMA in cell culture diminished gradually after day 3 posttreatment. 7-Deaza-2′-CMA showed no detectable cellular toxicity (CC 50 〉 50 μM), and the antiviral effect in culture was stable for 〉 6 days posttreatment. Computational molecular analyses revealed that compared to the other two compounds, 7-deaza-2′-CMA formed a large cluster near the active site of the TBEV polymerase. High antiviral activity and low cytotoxicity suggest that 7-deaza-2′-CMA is a promising candidate for further investigation as a potential therapeutic agent in treating TBEV infection.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.00807-15
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2015
    detail.hit.zdb_id: 1496156-8
    detail.hit.zdb_id: 217602-6
    SSG: 12
    SSG: 15,3
    Location Call Number Limitation Availability
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    Online Resource
  • 5
    Online Resource
    Online Resource
    Long-Term Outcomes of First-Admission Psychosis: A Naturalistic 21-Year Follow-Up Study of Symptomatic, Functional and Personal Recovery and Their Baseline Predictors
    Oxford University Press (OUP) ; 2022
    In:  Schizophrenia Bulletin Vol. 48, No. 3 ( 2022-05-07), p. 631-642
    Details
    In: Schizophrenia Bulletin, Oxford University Press (OUP), Vol. 48, No. 3 ( 2022-05-07), p. 631-642
    Abstract: This study was aimed at characterizing long-term outcomes of first-admission psychosis and examining their baseline predictors. Participants were assessed at baseline for 38 candidate predictors and re-assessed after a median follow-up of 21 years for symptomatic, functional, and personal recovery. Associations between the predictors and the outcomes were examined using univariate and multivariate Cox regression models. At baseline, 623 subjects were assessed for eligibility, 510 met the inclusion/exclusion criteria and 243 were successfully followed-up (57.3% of the survivors). At follow-up, the percentages of subjects achieving symptomatic, functional, and personal recovery were 51.9%, 52.7%, and 51.9%, respectively; 74.2% met at least one recovery criterion and 32.5% met all three recovery criteria. Univariate analysis showed that outcomes were predicted by a broad range of variables, including sociodemographics, familial risk, early risk factors, premorbid functioning, triggering factors, illness-onset features, neurological abnormalities, deficit symptoms and early response to treatment. Many of the univariate predictors became nonsignificant when entered into a hierarchical multivariate model, indicating a substantial degree of interdependence. Each single outcome component was independently predicted by parental socioeconomic status, family history of schizophrenia spectrum disorders, early developmental delay, childhood adversity, and mild drug use. Spontaneous dyskinesia/parkinsonism, neurological soft signs and completion of high school remained specific predictors of symptomatic, functional, and personal outcomes, respectively. Predictors explained between 27.5% and 34.3% of the variance in the outcomes. In conclusion, our results indicate a strong potential for background and first-episode characteristics in predicting long-term outcomes of psychotic disorders, which may inform future intervention research.
    Type of Medium: Online Resource
    ISSN: 0586-7614 , 1745-1701
    URL: Article
    DOI: 10.1093/schbul/sbab145
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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    detail.hit.zdb_id: 439173-1
    SSG: 15,3
    Location Call Number Limitation Availability
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