Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The domain of solid organ transplantation is characterized by the use of variable drug combinations with drug-drug interactions, and the presence of two genomes, that of the transplanted organ and that of the receiver, which can be involved in the pharmacogenetics of these drugs. This paper is a literature review of the impact of the genetic polymorphisms of the metabolic enzymes, efflux transporters and therapeutic targets of the main immunosuppressive drugs (cyclosporine, tacrolimus, sirolimus and mycophenolate) on the dose-concentration and concentration-effect relationships of these drugs. The polymorphisms of metabolic enzymes have significant effects on the pharmacokinetics of all these drugs, but the clinical trials for validating treatment individualization based on these genetic differences are still lacking. It should be noted that the influence of the donor's genome has seldom been studied and has been found to be significant in liver transplant recipients. The influence of efflux transporter genes polymorphisms, in particular of P-glycoprotein and MPR2, is controversial. As for the polymorphisms of the drug targets genes, either they have not been reported (calcineurin, mTOR), or their influence has only been the subject of a few preliminary studies (IMPDH2). The pharmacogenetics of immunosuppressants is thus still an open field for investigations and potential therapeutic progress.
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PMID:[Pharmacogenetics and immunosuppressor drugs: impact and clinical interest in transplantation]. 1807 70

Norovirus is a major cause of acute gastroenteritis worldwide and has emerged as an important issue of chronic infection in transplantation patients. Since no approved antiviral is available, we evaluated the effects of different immunosuppressants and ribavirin on norovirus and explored their mechanisms of action by using a human norovirus (HuNV) replicon-harboring model and a surrogate murine norovirus (MNV) infectious model. The roles of the corresponding drug targets were investigated by gain- or loss-of-function approaches. We found that the calcineurin inhibitors cyclosporine (CsA) and tacrolimus (FK506) moderately inhibited HuNV replication. Gene silencing of their cellular targets, cyclophilin A, FKBP12, and calcineurin, significantly inhibited HuNV replication. A low concentration, therapeutically speaking, of mycophenolic acid (MPA), an uncompetitive IMP dehydrogenase (IMPDH) inhibitor, potently and rapidly inhibited norovirus replication and ultimately cleared HuNV replicons without inducible resistance following long-term drug exposure. Knockdown of the MPA cellular targets IMPDH1 and IMPDH2 suppressed HuNV replication. Consistent with the nucleotide-synthesizing function of IMPDH, exogenous guanosine counteracted the antinorovirus effects of MPA. Furthermore, the competitive IMPDH inhibitor ribavirin efficiently inhibited norovirus and resulted in an additive effect when combined with immunosuppressants. The results from this study demonstrate that calcineurin phosphatase activity and IMPDH guanine synthase activity are crucial in sustaining norovirus infection; thus, they can be therapeutically targeted. Our results suggest that MPA shall be preferentially considered immunosuppressive medication for transplantation patients at risk of norovirus infection, whereas ribavirin represents as a potential antiviral for both immunocompromised and immunocompetent patients with norovirus gastroenteritis.
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PMID:Inhibition of Calcineurin or IMP Dehydrogenase Exerts Moderate to Potent Antiviral Activity against Norovirus Replication. 2880 16