Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.30.2 (endonuclease)
 18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cisplatin is an anticancer drug currently used in the treatment of genital and head and neck tumors. Its use in these and other types of tumors is narrowed by onset of chemoresistance and severe undesired side effects, like as nephro- and ototoxicity, whose mechanisms of action are only partially understood. In the present study we investigated the effects of cisplatin (cis-dichlorodiaminoplatin, CDDP) on a cell line (OC-k3) developed from organs of Corti of transgenic mice. We observed at 48 h that cell death due to cisplatin was time and concentration-dependent. The cell death displayed some morphological hallmarks of apoptosis, including nuclear fragmentation into several large nuclear fragments, surrounded by a rearranged and thickened actin cytoskeleton. No DNA laddering was detected, suggesting absence of endonuclease activity, nor annexin V positivity, suggesting absence of phosphatidylserine externalization. Several molecules protected the cells against CDDP induced cytotoxicity, including methionine, suramin and PD98059. Methionine reduced CDDP-uptake, while suramin, a polycathionic compound a specifically binding external proteins, did not. This finding suggested that suramin could exert its protective effect by acting on an intracellular transduction pathway. We tested this hypothesis by studying the effect of suramin and PD98059, a MEK inhibitor, on the mitogen activated protein kinase (MAPK) cascade. After CDDP treatment, we found an increase of phosphorylation of extracellular regulated kinases (ERK)1/2, that could be inhibited by PD98059 and suramin. These data suggest that ERK pathways can play a role in mediating the cell death induction in presence of a CDDP challenge.
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PMID:Cisplatin cytotoxicity in organ of Corti-derived immortalized cells. 1724 13

In this review, we will discuss drug design based on proven and potential anti-influenza drug targets including viral hemagglutinin (HA), neuraminidase (NA), M2 ion channel, 3P polymerase complex, and host factors such as kinases. We have summarized influenza inhibitors based on their mode of actions. For instance, included are descriptions of (1) inhibitors of HA cleavage, such as nafamostat, camostat, gabexate, epsilon-aminocapronic acid and aprotinin, (2) inhibitors of fusion and entry, such as benzoquinones and hydroquinones, CL 385319, BMY-27709, stachyflin, and their analogues, (3) inhibitors of viral RNPs/polymerase/endonuclease, such as T-705, L-735,822, flutimide and their analogues, (4) inhibitors of MEK, such as PD 0325901, CI-1040 and ARRY-142886, and (5) inhibitors of NA such as DANA, FANA, zanamivir, and oseltamivir, etc. Although amantadine and rimantadine are not recommended for treating influenza virus infections because of drug resistance problem, these viral M2 ion channel blockers established a proof-of-concept that the endocytosis of virion into host cells can be a valid drug target because M2 protein is involved in the endocytosis process. The influenza polymerase complex not only catalyzes RNA polymerization but also encodes the "cap snatching" activity. After being exported from the nucleus to the cytoplasm, the newly synthesized vRNPs are assembled into virions at the plasma membrane. The progeny virions will then leave the host cells through the action of NA. The strategies for discovery of small molecule inhibitors of influenza virus replication based on each particular mechanism will be discussed. Finally, the lessons learned from the design of NA inhibitors (NAI) are also included. Many exciting opportunities await the cadre of virologists, medicinal chemists, and pharmacologists to design novel influenza drugs with favorable pharmacological and pharmacokinetic properties to combat this threatening infectious disease.
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PMID:Strategies of development of antiviral agents directed against influenza virus replication. 1822 Jul 89