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2- and N6-functionalized adenosine-5'-diphosphate analogs for the inhibition of mortalin.

ABSTRACT: Our early efforts to find a covalent inhibitor of mortalin, a member of the 70 kD heat shock protein (Hsp70) family, led us to solve the structure of the mortalin nucleotide-binding domain (NBD) in complex with N6-propargyladenosine-5'-diphosphate. The acquired structure emphasizes the ability of the nucleotide-binding pocket to accommodate modified ADP compounds. A library of ADP analogs modified at either the 2- or N6-positions of adenosine was screened against the mortalin-NBD. Competitive inhibition and binding assays of the analogs demonstrate that modifications at the 2- or N6-positions have potential to bind and inhibit mortalin uniquely compared to other Hsp70 homologs, and that modifications at the 2-position confer the greatest selectivity in binding and inhibition of the mortalin-NBD.

SUBMITTER: Moseng MA

PROVIDER: S-EPMC6690775 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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2- and N6-functionalized adenosine-5'-diphosphate analogs for the inhibition of mortalin.

Moseng Mitchell A MA Nix Jay C JC Page Richard C RC

FEBS letters 20190618 15

Our early efforts to find a covalent inhibitor of mortalin, a member of the 70 kD heat shock protein (Hsp70) family, led us to solve the structure of the mortalin nucleotide-binding domain (NBD) in complex with N6-propargyladenosine-5'-diphosphate. The acquired structure emphasizes the ability of the nucleotide-binding pocket to accommodate modified ADP compounds. A library of ADP analogs modified at either the 2- or N6-positions of adenosine was screened against the mortalin-NBD. Competitive in ...[more]

PMID: 31177526

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Project description:BackgroundAcute respiratory distress syndrome (ARDS) is a severe form of lung injury that frequently occurs during pneumonia and sepsis. Lung inflammation in ARDS patients may have deleterious effects on remote organs such as the kidney. The nuclear enzyme poly(adenosine diphosphate-ribose) polymerase (PARP) enhances the nuclear factor (NF)-?B-dependent transcription of inflammatory cytokines. This study was conducted to elucidate two questions: first, whether the activation of PARP and NF-?B mediates the renal inflammation secondary to the lipopolysaccharide (LPS)-induced acute lung inflammation; second, whether a PARP inhibitor, 3-aminobenzamide (3-AB), attenuates lung and kidney inflammation by inhibiting NF-?B-dependent proinflammatory cytokines.MethodsMale Sprague-Dawley rats were anesthetized, ventilated, and divided into three groups; a control group (n?=?8); an LPS group (n?=?12) intratracheally instilled with LPS (16 mg/kg), and an LPS?+?3-AB group (n?=?12) given the same dose of LPS by the same method followed by an intravenous injection of 3-AB (20 mg/kg). Hemodynamics, arterial blood gas, and the plasma levels of lactate, creatinine and potassium were measured at 0,1,2,3, and 4 h after treatment. The lung wet/dry ratio was measured at 4 h. The mRNA expression of tumor necrosis factor (TNF)-?, interleukin (IL)-1? and IL-6 in the lung and kidney were measured by TaqMan real-time PCR. PARP and NF-?B in the lung and kidney were histologically examined by immunostaining and assigned expression scores.ResultsLPS induced metabolic acidosis, hypotension, hypoxemia, increased the lung wet/dry ratio, increased the plasma levels of creatinine and potassium, and increased the cytokine mRNA expressions in the lung and kidney. All of these effects were associated with strong expression of PARP and NF-?B. Treatment with 3-AB prevented the LPS-induced metabolic acidosis and hypotension, reduced the plasma levels of lactate, creatinine and potassium, reduced the cytokine mRNA expressions, reduced the expression of PARP and NF-?B, improved pulmonary edema and oxygenation and preserved renal function.ConclusionsThe PARP inhibition attenuated lung-kidney crosstalk induced by intratracheal LPS instillation, partly via an inhibition of NF-?B dependent proinflammatory cytokines.

Dataset Information

2- and N6-functionalized adenosine-5'-diphosphate analogs for the inhibition of mortalin.

Publications

2- and N6-functionalized adenosine-5'-diphosphate analogs for the inhibition of mortalin.

Similar Datasets

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