Ubiquinone 9 (UQ9), the expected product of the long-chain solanesyl diphosphate synthase of Trypanosoma brucei (TbSPPS), has a central role in reoxidation of reducing equivalents in the mitochondrion of T. brucei. The ablation of TbSPPS gene expression by RNA interference increased the generation of reactive oxygen species and reduced cell growth and oxygen consumption. The addition of glycerol to the culture medium exacerbated the phenotype by blocking its endogenous generation and excretion. The participation of TbSPPS in UQ synthesis was further confirmed by growth rescue using UQ with 10 isoprenyl subunits (UQ10). Furthermore, the survival of infected mice was prolonged upon the downregulation of TbSPPS and/or the addition of glycerol to drinking water. TbSPPS is inhibited by 1-[(n-oct-1-ylamino)ethyl] 1,1-bisphosphonic acid, and treatment with this compound was lethal for the cells. The findings that both UQ9 and ATP pools were severely depleted by the drug and that exogenous UQ10 was able to fully rescue growth of the inhibited parasites strongly suggest that TbSPPS and UQ synthesis are the main targets of the drug. These two strategies highlight the importance of TbSPPS for T. brucei, justifying further efforts to validate it as a new drug target.

• MeSH
• alkyltransferasy a aryltransferasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• doxycyklin terapeutické užití   MeSH
• glycerol terapeutické užití   MeSH
• indoly MeSH
• inhibitory enzymů farmakologie   MeSH
• maleimidy MeSH
• myši MeSH
• nitrily farmakokinetika   farmakologie   MeSH
• protozoální proteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• pyridiny farmakokinetika   farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• stadia vývoje * MeSH
• Trypanosoma brucei brucei enzymologie   růst a vývoj   patogenita   MeSH
• trypanozomiáza farmakoterapie   MeSH
• ubichinon biosyntéza   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3-(4-fluorophenylethylamino)-1-methyl-4-(2-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione MeSH Prohlížeč
• alkyltransferasy a aryltransferasy MeSH
• doxycyklin MeSH
• glycerol MeSH
• indoly MeSH
• inhibitory enzymů MeSH
• maleimidy MeSH
• nitrily MeSH
• protozoální proteiny MeSH
• pyridiny MeSH
• reaktivní formy kyslíku MeSH
• trans-octaprenyltranstransferase MeSH Prohlížeč
• ubichinon MeSH

The article summarizes the basic facts about the pharmacokinetic profile, metabolism and drug interactions of rilpivirine (RPV). This is the latest orally administered second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for antiretroviral-naive patients with HIV-1 infection. Conformational flexibility and adaptability are the factors that dominantly determine the high resistance barrier of RPV and are the unique features of diarylpyrimidine inhibitors (DAPY inhibitors - 2nd generation NNRTIs). Multicentre studies ECHO and THRIVE are also reviewed. Current guidelines for the treatment of HIV/AIDS are mentioned as well as the role of RPV in current therapeutic regimens.

• MeSH
• HIV infekce farmakoterapie   MeSH
• HIV reverzní transkriptasa antagonisté a inhibitory   MeSH
• HIV-1 * MeSH
• lidé MeSH
• nitrily škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• pyrimidiny škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• rilpivirin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• HIV reverzní transkriptasa MeSH
• nitrily MeSH
• pyrimidiny MeSH
• rilpivirin MeSH