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A Pseudouridine Isoxazolidinyl Nucleoside Analogue Structural Analysis: A Morphological Approach.

ABSTRACT: An in silico study has been conducted upon (3'RS,5'SR)-5-[2'-benzyl-5'-hydroxymethyl-1',2'-isoxazolidin-3'-yl]uracil through a molecular dynamics/docking approach that highlights its potential inhibitory activity upon the wild-type pseudouridine 5'-monophosphate glycosidase. The crystal structure of this compound has been solved by means of X-ray single crystal diffraction and the data inferred were used to predict its crystal morphology. These data were compared with optical microscopy images and confirmed the validity of the computed models. This robust approach, already used for several other different compounds, provides a fast and reliable tool to standardize a crystallization method in order to get similar and good quality crystals. As different crystal shapes could be associated with different polymorphic forms, this method could be considered a fast and cheap screening to choose among different and coexistent polymorphic forms. Furthermore, a match with the original crystal structure of pseudouridine 5'-monophosphate is provided.

SUBMITTER: Floresta G

PROVIDER: S-EPMC6321120 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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A Pseudouridine Isoxazolidinyl Nucleoside Analogue Structural Analysis: A Morphological Approach.

Floresta Giuseppe G Pistarà Venerando V Christensen Kirsten E KE Amata Emanuele E Marrazzo Agostino A Gentile Davide D Rescifina Antonio A Punzo Francesco F

Molecules (Basel, Switzerland) 20181219 12

An in silico study has been conducted upon (3'<i>RS</i>,5'<i>SR</i>)-5-[2'-benzyl-5'-hydroxymethyl-1',2'-isoxazolidin-3'-yl]uracil through a molecular dynamics/docking approach that highlights its potential inhibitory activity upon the wild-type pseudouridine 5'-monophosphate glycosidase. The crystal structure of this compound has been solved by means of X-ray single crystal diffraction and the data inferred were used to predict its crystal morphology. These data were compared with optical micro ...[more]

PMID: 30572684

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Project description:To determine the relationship between host immunity and the characteristics of viral infection or nucleoside analogues (NAs) themselves in patients with chronic hepatitis B (CHB) receiving NA therapy.Fifty-two hepatitis B envelope antigen (HBeAg) positive CHB patients were enrolled and divided equally into two groups. One group received telbivudine (LDT, 600 mg/d), and the other group received lamivudine (LAM, 100 mg/d). Clinical, virological and immunological parameters were assessed at the baseline and at 4, 12, 24, 36 and 48 wk.Both groups achieved significant hepatitis B virus (HBV) replication inhibition and alanine aminotransferase normalization at 48 wk. At the baseline, compared to healthy controls, CHB patients had a lower circulating CD8 T cell frequency (29.44% ± 11.55% vs 37.17% ± 7.30%, P = 0.03) and higher frequencies of programmed death 1 positive CD8 T cells (PD-1+ CD8 T) (16.48% ± 10.82% vs 7.02% ± 3.62%, P = 0.0001) and CD4+ CD25+ FoxP3+ T regulatory cells (Tregs) (23.64% ± 9.38% vs 13.60% ± 6.06%, P = 0.001). On therapy, at the beginning 24 wk with the levels of hepatitis B virus deoxyribonucleic acid (HBV DNA) and HBeAg declining, the frequencies of PD-1+ CD8 T cells and Treg cells gradually and significantly declined at 12 and 24 wk in both therapy groups. At treatment week 4, patients treated with LDT had a lower frequency of PD-1+ CD8 T cells compared to patients treated with LAM (10.08% ± 6.83% vs 20.51% ± 20.96%, P = 0.02). The frequency of PD-1+ CD8 T cells in all of the CHB patients was significantly correlated with both the HBV DNA level (r = 0.45, P = 0.01) and HBeAg level (r = 0.47, P = 0.01) at treatment week 24, but the frequency of Treg cells was only significantly correlated with the HBeAg level (r = 0.44,P = 0.02). Furthermore, the ability of CD8 T cells to secrete pro-inflammatory cytokines was partially restored after 24 wk of therapy.NA-mediated HBV suppression could down-regulate the production of negative regulators of host immunity during the first 24 wk of therapy and could partially restore the ability of CD8 T cells to secrete pro-inflammatory cytokines. This immune modulating response may be correlated with the levels of both HBV DNA and HBeAg.

Dataset Information

A Pseudouridine Isoxazolidinyl Nucleoside Analogue Structural Analysis: A Morphological Approach.

Publications

A Pseudouridine Isoxazolidinyl Nucleoside Analogue Structural Analysis: A Morphological Approach.

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