scholarly journals Staphylococcus aureustargets the purine salvage pathway to kill phagocytes

2018 ◽  
Vol 115 (26) ◽  
pp. 6846-6851 ◽  
Author(s):  
Volker Winstel ◽  
Dominique Missiakas ◽  
Olaf Schneewind
Keyword(s):  
Caspase 3 ◽  
Staphylococcal Nuclease ◽  
Adenosine Kinase ◽  
Nucleoside Transporter ◽  
Salvage Pathway ◽  
Purine Salvage ◽  
Antibiotic Resistant ◽  
Equilibrative Nucleoside Transporter ◽  
Extracellular Traps ◽  
Invasive Infections

Staphylococcus aureuscolonizes large segments of the human population and causes invasive infections due to its ability to escape phagocytic clearance. During infection, staphylococcal nuclease and adenosine synthase A convert neutrophil extracellular traps to deoxyadenosine (dAdo), which kills phagocytes. The mechanism whereby staphylococcal dAdo intoxicates phagocytes is not known. Here we used CRISPR-Cas9 mutagenesis to show that phagocyte intoxication involves uptake of dAdo via the human equilibrative nucleoside transporter 1, dAdo conversion to dAMP by deoxycytidine kinase and adenosine kinase, and signaling via subsequent dATP formation to activate caspase-3–induced cell death. Disruption of this signaling cascade confers resistance to dAdo-induced intoxication of phagocytes and may provide therapeutic opportunities for the treatment of infections caused by antibiotic-resistantS. aureusstrains.

scholarly journals Transport of purines and purine salvage pathway inhibitors by the Plasmodium falciparum equilibrative nucleoside transporter PfENT1

2010 ◽  
Vol 169 (1) ◽  
pp. 40-49 ◽  
Author(s):  
Paul M. Riegelhaupt ◽  
María B. Cassera ◽  
Richard F.G. Fröhlich ◽  
Keith Z. Hazleton ◽  
Jonathan J. Hefter ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Nucleoside Transporter ◽  
Salvage Pathway ◽  
Purine Salvage ◽  
Equilibrative Nucleoside Transporter

scholarly journals Possible Role of Adenosine in COVID-19 Pathogenesis and Therapeutic Opportunities

2020 ◽  
Vol 11 ◽  
Author(s):  
Jonathan D. Geiger ◽  
Nabab Khan ◽  
Madhuvika Murugan ◽  
Detlev Boison
Keyword(s):  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Adenosine Kinase ◽  
Nucleoside Transporter ◽  
The Novel ◽  
Equilibrative Nucleoside Transporter ◽  
Novel Coronavirus ◽  
End Stage

The outbreak of the novel coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) requires urgent clinical interventions. Crucial clinical needs are: 1) prevention of infection and spread of the virus within lung epithelia and between people, 2) attenuation of excessive lung injury in Advanced Respiratory Distress Syndrome, which develops during the end stage of the disease, and 3) prevention of thrombosis associated with SARS-CoV-2 infection. Adenosine and the key adenosine regulators adenosine deaminase (ADA), adenosine kinase (ADK), and equilibrative nucleoside transporter 1 may play a role in COVID-19 pathogenesis. Here, we highlight 1) the non-enzymatic role of ADA by which it might out-compete the virus (SARS-CoV-2) for binding to the CD26 receptor, 2) the enzymatic roles of ADK and ADA to increase adenosine levels and ameliorate Advanced Respiratory Distress Syndrome, and 3) inhibition of adenosine transporters to reduce platelet activation, thrombosis and improve COVID-19 outcomes. Depending on the stage of exposure to and infection by SARS-CoV-2, enhancing adenosine levels by targeting key adenosine regulators such as ADA, ADK and equilibrative nucleoside transporter 1 might find therapeutic use against COVID-19 and warrants further investigation.

scholarly journals 4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma Brucei

2021 ◽  
Vol 9 (4) ◽  
pp. 826
Author(s):  
Dorien Mabille ◽  
Camila Cardoso Santos ◽  
Rik Hendrickx ◽  
Mathieu Claes ◽  
Peter Takac ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Drug Target ◽  
Drug Targets ◽  
De Novo ◽  
Treatment Options ◽  
Adenosine Kinase ◽  
Nucleoside Analogues ◽  
Purine Salvage ◽  
Interacting Protein ◽  
Novel Drug

Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets. The activity of known nucleoside analogues such as tubercidin and cordycepin led to the development of a series of C7-substituted nucleoside analogues. Here, we use RNA interference (RNAi) libraries to gain insight into the mode-of-action of these novel nucleoside analogues. Whole-genome RNAi screening revealed the involvement of adenosine kinase and 4E interacting protein into the mode-of-action of certain antitrypanosomal nucleoside analogues. Using RNAi lines and gene-deficient parasites, 4E interacting protein was found to be essential for parasite growth and infectivity in the vertebrate host. The essential nature of this gene product and involvement in the activity of certain nucleoside analogues indicates that it represents a potential novel drug target.

Contribution of equilibrative nucleoside transporter (ENT) 2 to fluorouracil transport in rat placental trophoblast cells

2017 ◽  
Vol 32 (2) ◽  
pp. 151-156 ◽  
Author(s):  
Akinori Takagi ◽  
Tomohiro Nishimura ◽  
Tomoya Akashi ◽  
Masatoshi Tomi ◽  
Emi Nakashima
Keyword(s):  
Nucleoside Transporter ◽  
Trophoblast Cells ◽  
Equilibrative Nucleoside Transporter

Nucleoside Transporter-guided Cytarabine Conjugated Liposomes for Intracellular Methotrexate Delivery and Cooperative Choriocarcinoma Therapy

2021 ◽  
Author(s):  
Weidong Fei ◽  
Yunchun Zhao ◽  
Xiaodong Wu ◽  
Dongli Sun ◽  
Yao Yao ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Rational Design ◽  
High Efficiency ◽  
Nucleoside Transporter ◽  
Childbearing Age ◽  
Equilibrative Nucleoside Transporter ◽  
Choriocarcinoma Cells ◽  
Tumor Accumulation ◽  
Novel Strategy ◽  
Distribution Studies

Abstract The gestational trophoblastic tumor seriously endangers child productive needs and the health of women in childbearing age. Nanodrug-based therapy mediated by transporters provides novel strategy for the treatment of trophoblastic tumors. Focus on the overexpressed human equilibrative nucleoside transporter 1 (ENT1) on the membrane of choriocarcinoma cells (JEG-3), the cytarabine (Cy, a substrate of ENT1) grafted liposome (Cy-Lipo) was introduced for targeted delivery of methotrexate (Cy-Lipo@MTX) for choriocarcinoma therapy in this study. The ENT1 has high affinity for Cy-Lipo and can mediate the endocytosis of the designed nanovehicles into JEG-3 cells. The ENT1 protein maintains its transporting function through circulation and regeneration during endocytosis. Therefore, Cy-Lipo-based formulations achieved high tumor accumulation and retention in pharmacokinetic and distribution studies. More importantly, the designed Cy-lipid conjugation exhibited a synergistic therapeutic effect on choriocarcinoma. Finally, Cy-Lipo@MTX exerts an extremely powerful anti-choriocarcinoma effect with fewer side effects. This study suggests that the overexpressed ENT1 on choriocarcinoma cells holds a great potential to be a high-efficiency target for the rational design of active targeting nanotherapeutics.

scholarly journals The role of the equilibrative nucleoside transporter 1 on tissue and fetal distribution of ribavirin in the mouse

2016 ◽  
Vol 37 (6) ◽  
pp. 336-344 ◽  
Author(s):  
Christopher J. Endres ◽  
Aaron M. Moss ◽  
Kazuya Ishida ◽  
Rajgopal Govindarajan ◽  
Jashvant D. Unadkat
Keyword(s):  
Nucleoside Transporter ◽  
Equilibrative Nucleoside Transporter
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