Q88340365
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Acyclic nucleoside phosphonates (ANPs) are a recognized class of antiviral and anticancer agents. Since the discovery of ANPs in the mid-1980s, ANPs have gained recognition in pharmaceutical research. Approvals of cidofovir (Vistide®) in 1996 and especially of tenofovir (disoproxyl fumarate, Viread®) in 2001 were important milestones in research of ANPs. It became clear that this class of antivirals has a full potential for the use in human medicine. The biological activity of ANPs is not restricted to antiviral and anticancer effects. This review highlights novel types of ANPs with antimalarial properties. The malarial parasites Plasmodium falciparum (Pf) and P. vivax (Pv) lack de novo pathway for synthesis of purine bases and rely on a salvage pathway enzyme, hypoxanthineguanine-( xanthine) phosphoribosyltransferase (HG(X)PRT) for the synthesis of 6-oxopurine nucleoside monophosphates. Specific ANPs can act as analogues of the enzymatic reaction products. They inhibit PfHGXPRT and/or PvHGPRT and show an antiplasmodial activity in vitro. In particular aza-ANP and bisphosphonate analogues were shown to become promising potential antimalarials.
- Klíčová slova
- 6-oxopurinfosforibosyltransferasa,
- MeSH
- antimalarika * farmakokinetika farmakologie chemie klasifikace terapeutické užití MeSH
- antivirové látky farmakokinetika farmakologie chemie klasifikace terapeutické užití MeSH
- inhibitory enzymů terapeutické užití MeSH
- lidé MeSH
- malárie * farmakoterapie MeSH
- nukleotidy farmakokinetika farmakologie chemie klasifikace terapeutické užití MeSH
- pentosyltransferasy farmakokinetika farmakologie chemie terapeutické užití MeSH
- Plasmodium účinky léků MeSH
- prekurzory léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
The malarial parasite Plasmodium falciparum (Pf) lacks the de novo pathway and relies on the salvage enzyme, hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT), for the synthesis of the 6-oxopurine nucleoside monophosphates. Specific acyclic nucleoside phosphonates (ANPs) inhibit PfHGXPRT and possess anti-plasmodial activity. Two series of novel branched ANPs derived from 9-[2-(2-phosphonoethoxy)ethyl]purines were synthesized to investigate their inhibition of PfHGXPRT and human HGPRT. The best inhibitor of PfHGXPRT has a K(i) of 1 microM. The data showed that both the position and nature of the hydrophobic substituent change the potency and selectivity of the ANPs.
- MeSH
- antimalarika farmakologie chemická syntéza chemie MeSH
- inhibitory enzymů chemická syntéza chemie farmakologie MeSH
- katalytická doména MeSH
- lidé MeSH
- organofosfonáty chemie MeSH
- pentosyltransferasy antagonisté a inhibitory metabolismus MeSH
- Plasmodium falciparum enzymologie MeSH
- počítačová simulace MeSH
- puriny farmakologie chemická syntéza chemie MeSH
- racionální návrh léčiv MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- adenosin analogy a deriváty terapeutické užití MeSH
- nádory terapie MeSH
- virové nemoci terapie MeSH
- Publikační typ
- kongresy MeSH
