Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the foremost causative agents of malaria. Due to the development of resistance to current antimalarial medications, new drugs for this parasitic disease need to be discovered. The activity of hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase, HG[X]PRT, is reported to be essential for the growth of both of these parasites, making it an excellent target for antimalarial drug discovery. Here, we have used rational structure-based methods to design an inhibitor, [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine, of PvHGPRT and PfHGXPRT that has Ki values of 8 and 7 nM, respectively, for these two enzymes. The crystal structure of PvHGPRT in complex with this compound has been determined to 2.85 Å resolution. The corresponding complex with human HGPRT was also obtained to allow a direct comparison of the binding modes of this compound with the two enzymes. The tetra-(ethyl l-phenylalanine) tetraamide prodrug of this compound was synthesized, and it has an IC50 of 11.7 ± 3.2 μM against Pf lines grown in culture and a CC50 in human A549 cell lines of 102 ± 11 μM, thus giving it a ∼10-fold selectivity index.

• MeSH
• antimalarika chemie   farmakologie   MeSH
• bisfosfonáty chemie   farmakologie   MeSH
• hypoxanthinfosforibosyltransferasa antagonisté a inhibitory   chemie   metabolismus   MeSH
• katalytická doména MeSH
• konformace proteinů MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• molekulární modely MeSH
• pentosyltransferasy antagonisté a inhibitory   chemie   metabolismus   MeSH
• Plasmodium vivax enzymologie   MeSH
• proteiny z Escherichia coli chemie   MeSH
• racionální návrh léčiv MeSH
• techniky syntetické chemie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

V kazuistike opisujeme prípad 49-ročného muža od detstva morbídne obézneho (BMI 40 kg/m2), s artériovou hypertenziou (asi od 15 rokov, liečená od roku 2004), dyslipidémiou (od roku 2006), diabetes mellitus 2. typu (od roku 2006, na inzulinoterapii od roku 2008) a fajčením (do roku 2011, 20 cigariet denne). Liečba: 16 druhov liekov, 8 na hypertenziu, statín, liečba diabetu, aspirín, alopurinol. V roku 2010 (ako 45-ročný) hospitalizovaný na našej klinike pre dyspnoe a bolesti na hrudníku s hodnotou krvného tlaku 180/110 mm Hg (zistené srdcové zlyhávanie s ejekčnou frakciou ĽK 33 %, vo funkčnej triede NYHA II, echokardiograficky: ľavá predsieň: 46 mm, rozmer ľavej komory v diastole: 70 mm, interventrikulárne septum: 12 mm, hypokinéza septa, dopplerovská ultrasonografia artérií dolných končatín (kalcifikácie, difúzne aterosklerotické zmeny, neprítomná stenóza), CT koronárna angiografia (signifikantná stenóza ľavej koronárnej artérie). Zahájená liečba perorálny furosemid 40 mg denne. V máji roku 2011 hospitalizovaný pre akútny koronárny syndróm: akútny NSTEMI spodnej steny (koronarografia: 2-cievne postihnutie, realizovaná PKI, implantovaný DES – ramus circumflexus, paroxyzmus fibrilácie predsiení, funkčná trieda NYHA III, ľavokomorová ejekčná frakcia: 30 %, pľúcna hypertenzia). V roku 2012 realizovaná renálna denervácia pre rezistentnú hypertenziu, implantovaný karotický stent pre stenózu karotickej artérie, prítomná diabetická nefropatia (KDOQI 3. stupňa, GF 40 ml/min). V auguste roku 2014 hospitalizovaný na našej klinike pre pľúcny edém, kardiogénny šok, akútnu ischémiu pravého predkolenia pri periférnej embolizácii, prítomný atriálny flutter, zhoršenie renálnych parametrov, echokardiograficky: ľavá predsieň: 55 mm, rozmer ľavej komory: 75 mm, akinéza septa a zadnej steny, oklúzia artérií pravej dolnej končatiny (vzhľadom na vážny stav pacienta kontraindikovaná angiochirurgická intervencia, zvažovaná amputácia končatiny z vitálnej indikácie), pacient zomrel po 4 dňoch hospitalizácie na intenzívnej jednotke po neúspešnej liečbe. Kombinácia ochorení diabetes, hypertenzia a ischemická choroba srdca je častá a prognosticky vážna. Diabetes zvyšuje kardiovaskulárnu morbiditu a mortalitu, a preto by sme mali hľadať diabetes u všetkých kardiovaskulárnych pacientov.

The case study describes a case of 49-year-old man with morbid obesity since childhood (BMI 40 kg/m2), arterial hypertension (approx. since aged 15, treated since 2004), dyslipidemia (since 2006), type 2 diabetes mellitus (since 2006, on insulin therapy since 2008) and smoking (until 2011, 20 cigarettes a day). Treatment: 16 types of medication, 8 for hypertension, statin, therapy for diabetes, aspirin, allopurinol. In 2010 (when aged 45) hospitalized in our clinic with dyspnoea and chest pain with a high pressure reading of 180/110 mm Hg (identified symptoms of heart failure with LV ejection fraction of 33 %, in NYHA II functional class, echocardiographically: left atrium: 46 mm, left ventricular chamber size in diastole: 70 mm, interventricular septum: 12 mm, septal hypokinesis, Doppler ultrasonography of lower limb arteries (calcification, diffuse atherosclerotic changes, absent stenosis), CT coronary angiography (significant stenosis of the left coronary artery). Treatment started with 40 mg oral dose of furosemide daily. In May 2011 he was hospitalized with an acute coronary syndrome: acute NSTEMI of the inferior wall (coronarography: 2-vascular problems, implemented PKI, implanted DES – ramus circumflexus, paroxysmal atrial fibrillation, NYHA III functional class, left ventricular ejection fraction: 30 %, pulmonary hypertension). In 2012 renal denervation for resistant hypertension was carried out, carotid stent implanted for stenosis of the carotid artery, presence of diabetic nephropathy (KDOQI stage 3, GF 40 ml/min). In August 2014 admitted to our clinic with pulmonary oedema, cardiogenic shock, acute ischemia of the right calf with peripheral embolisation, presence of atrial flutter, impairment of renal parameters, echocardiographically: left atrium: 55 mm, left ventricle size: 75 mm, akinesis of the septum and posterior wall, occlusion of the right leg arteries (given the patient‘s serious state angio-surgical intervention was contraindicated, vitally indicated leg amputation considered), the patient died after 4 days of hospitalization in an intensive care unit after unsuccessful treatment. A combination of diabetes, hypertension and ischemic heart disease is frequent and prognostically serious. Diabetes increases cardiovascular morbidity and mortality and therefore we should check for diabetes in all cardiovascular patients.

• MeSH
• akutní koronární syndrom * terapie   MeSH
• diabetes mellitus 2. typu MeSH
• fatální výsledek MeSH
• hypertenze terapie   MeSH
• ischemická choroba srdeční MeSH
• kardiogenní šok diagnóza   terapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolický syndrom komplikace   MeSH
• morbidní obezita MeSH
• onemocnění periferních arterií * komplikace   MeSH
• péče o pacienty v kritickém stavu MeSH
• progrese nemoci MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Hypoxanthine-guanine-(xanthine) phosphoribosyltransferase (HG(X)PRT) is crucial for the survival of malarial parasites Plasmodium falciparum (Pf) and Plasmodium vivax (Pv). Acyclic nucleoside phosphonates (ANPs) are inhibitors of HG(X)PRT and arrest the growth of Pf in cell culture. Here, a novel class of ANPs containing trisubstituted nitrogen (aza-ANPs) has been synthesized. These compounds have a wide range of K(i) values and selectivity for human HGPRT, PfHGXPRT, and PvHGPRT. The most selective and potent inhibitor of PfHGXPRT is 9-[N-(3-methoxy-3-oxopropyl)-N-(2-phosphonoethyl)-2-aminoethyl]hypoxanthine (K(i) = 100 nM): no inhibition could be detected against the human enzyme. This compound exhibits the highest ever reported selectivity for PfHGXPRT compared to human HGPRT. For PvHGPRT, 9-[N-(2-carboxyethyl)-N-(2-phosphonoethyl)-2-aminoethyl]guanine has a K(i) of 50 nM, the best inhibitor discovered for this enzyme to date. Docking of these compounds into the known structures of human HGPRT in complex with ANP-based inhibitors suggests reasons for the variations in affinity, providing insights for the design of antimalarial drug candidates.

• MeSH
• antimalarika chemická syntéza   chemie   farmakologie   MeSH
• hypoxanthinfosforibosyltransferasa antagonisté a inhibitory   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• malárie farmakoterapie   MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• nukleosidy chemická syntéza   chemie   farmakologie   MeSH
• organofosfonáty farmakologie   chemická syntéza   chemie   MeSH
• pentosyltransferasy antagonisté a inhibitory   MeSH
• Plasmodium falciparum účinky léků   enzymologie   MeSH
• Plasmodium vivax účinky léků   enzymologie   MeSH
• racionální návrh léčiv MeSH
• substrátová specifita MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Protozoan parasites from the Plasmodiidae family are the causative agents of malaria. Inhibition of hypoxanthine-guanine-(xanthine) phosphoribosyltransferase (HG(X)PRT) has been suggested as a target for development of new anti-malarial therapeutics. Acyclic nucleoside phosphonates (ANPs) are potent and selective inhibitors of plasmodial HG(X)PRTs. A new series of ANPs, based on the chemical structure and inhibitory activity of three ANPs, 2-(phosphonoethoxy)ethyl with either guanine or hypoxanthine as the base (PEEG and PEEHx) and 3-hydroxy-2-(phosphonomethoxy)propyl with guanine as the base (HPMPG), were prepared. These compounds are stereoisomers of 3-fluoro-(2-phosphonoethoxy)propyl (FPEPs) and 3-fluoro-(2-phosphonomethoxy)propyl (FPMPs) analogues. Both the (R)- and (S)-isomers of these fluorinated derivatives have higher Ki values (by 10- to 1000-fold) for human HGPRT and Plasmodium falciparum HGXPRT than the non-fluorinated ANPs. Possible explanations for these changes in affinity are proposed based on docking studies using the known crystal structures of human HGPRT in complex with PEEG.

• MeSH
• antiprotozoální látky chemická syntéza   chemie   farmakologie   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• parazitické testy citlivosti MeSH
• pentosyltransferasy antagonisté a inhibitory   metabolismus   MeSH
• Plasmodium falciparum účinky léků   MeSH
• Plasmodium vivax účinky léků   MeSH
• puriny chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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

Acyclic nucleoside phosphonates (ANPs) are an important class of therapeutic drugs that act as antiviral agents by inhibiting viral DNA polymerases and reverse transcriptases. ANPs containing a 6-oxopurine unit instead of a 6-aminopurine or pyrimidine base are inhibitors of the purine salvage enzyme, hypoxanthine-guanine-[xanthine] phosphoribosyltransferase (HG[X]PRT). Such compounds, and their prodrugs, are able to arrest the growth of Plasmodium falciparum (Pf) in cell culture. A new series of ANPs were synthesized and tested as inhibitors of human HGPRT, PfHGXPRT, and Plasmodium vivax (Pv) HGPRT. The novelty of these compounds is that they contain a five-membered heterocycle (imidazoline, imidazole, or triazole) inserted between the acyclic linker(s) and the nucleobase, namely, 9-deazahypoxanthine. Five of the compounds were found to be micromolar inhibitors of PfHGXPRT and PvHGPRT, but no inhibition of human HGPRT was observed under the same assay conditions. This demonstrates selectivity of these types of compounds for the two parasitic enzymes compared to the human counterpart and confirms the importance of the chemical nature of the acyclic moiety in conferring affinity/selectivity for these three enzymes.

• MeSH
• antimalarika chemická syntéza   chemie   MeSH
• hypoxanthinfosforibosyltransferasa antagonisté a inhibitory   MeSH
• hypoxanthiny chemie   MeSH
• lidé MeSH
• molekulární modely MeSH
• nukleosidy chemická syntéza   chemie   MeSH
• organofosfonáty chemická syntéza   chemie   MeSH
• pentosyltransferasy antagonisté a inhibitory   MeSH
• Plasmodium falciparum enzymologie   MeSH
• Plasmodium vivax enzymologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Parasites of the Plasmodium genus are unable to produce purine nucleotides de novo and depend completely on the salvage pathway. This fact makes plasmodial hypoxanthine-guanine-(xanthine) phosphoribosyltransferase [HG(X)PRT] a valuable target for development of antimalarial agents. A series of nucleotide analogues was designed, synthesized and evaluated as potential inhibitors of Plasmodium falciparum HGXPRT, P. vivax HGPRT and human HGPRT. These novel nucleoside phosphonates have a pyrrolidine, piperidine or piperazine ring incorporated into the linker connecting the purine base to a phosphonate group(s) and exhibited a broad range of Ki values between 0.15 and 72 μM. The corresponding phosphoramidate prodrugs, able to cross cell membranes, have been synthesized and evaluated in a P. falciparum infected human erythrocyte assay. Of the eight prodrugs evaluated seven exhibited in vitro antimalarial activity with IC50 values within the range of 2.5-12.1 μM. The bis-phosphoramidate prodrug 13a with a mean (SD) IC50 of 2.5 ± 0.7 μM against the chloroquine-resistant P. falciparum W2 strain exhibited low cytotoxicity in the human hepatocellular liver carcinoma (HepG2) and normal human dermal fibroblasts (NHDF) cell lines at a concentration of 100 μM suggesting good selectivity for further structure-activity relationship investigations.

• MeSH
• antimalarika chemická syntéza   metabolismus   farmakologie   MeSH
• buněčné linie MeSH
• erytrocyty cytologie   metabolismus   parazitologie   MeSH
• inhibitory enzymů chemie   metabolismus   MeSH
• léková rezistence účinky léků   MeSH
• lidé MeSH
• nukleotidy chemie   metabolismus   MeSH
• pentosyltransferasy antagonisté a inhibitory   metabolismus   MeSH
• piperazin chemie   MeSH
• piperidiny chemie   MeSH
• Plasmodium falciparum účinky léků   enzymologie   MeSH
• Plasmodium vivax enzymologie   MeSH
• preklinické hodnocení léčiv MeSH
• prekurzory léčiv chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• protozoální proteiny antagonisté a inhibitory   metabolismus   MeSH
• pyrrolidiny chemie   MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The purine salvage enzyme, hypoxanthine-guanine-(xanthine) phosphoribosyltransferase [HG(X)PRT], catalyses the synthesis of the purine nucleoside monophosphates, IMP, GMP or XMP essential for DNA/RNA production. In protozoan parasites, such as Plasmodium, this is the only route available for their synthesis as they lack the de novo pathway which is present in human cells. Acyclic nucleoside phosphonates (ANPs), analogs of the purine nucleoside monophosphates, have been found to inhibit Plasmodium falciparum (Pf) HGXPRT and Plasmodium vivax (Pv) HGPRT with K(i) values as low as 100 nM. They arrest parasitemia in cell based assays with IC(50) values of the order of 1-10 μM. ANPs with phosphonoalkyl and phosphonoalkoxyalkyl moieties linking the purine base and phosphonate group were designed and synthesised to evaluate the influence of this linker on the potency and/or selectivity of the ANPs for the human and malarial enzymes. This data shows that variability in the linker, as well as the positioning of the oxygen in this linker, influences binding. The human enzyme binds the ANPs with K(i) values of 0.5 μM when the number of atoms in the linker was 5 or 6 atoms. However, the parasite enzymes have little affinity for such long chains unless oxygen is included in the three-position. In comparison, all three enzymes have little affinity for ANPs where the number of atoms linking the base and the phosphonate group is of the order of 2-3 atoms. The chemical nature of the purine base also effects the K(i) values. This data shows that both the linker and the purine base play an important role in the binding of the ANPs to these three enzymes.

• MeSH
• aktivace enzymů účinky léků   MeSH
• antimalarika chemická syntéza   chemie   farmakologie   MeSH
• kinetika MeSH
• lidé MeSH
• pentosyltransferasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• Plasmodium falciparum účinky léků   enzymologie   MeSH
• Plasmodium vivax účinky léků   enzymologie   MeSH
• protozoální proteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• puriny chemická syntéza   chemie   farmakologie   MeSH
• rekombinantní proteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Acyclic nucleoside phosphonates (ANPs) are a promising class of antimalarial therapeutic drug leads that exhibit a wide variety of Ki values for Plasmodium falciparum (Pf) and human hypoxanthine-guanine-(xanthine) phosphoribosyltransferases [HG(X)PRTs]. A novel series of ANPs, analogues of previously reported 2-(phosphonoethoxy)ethyl (PEE) and (R,S)-3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) derivatives, were designed and synthesized to evaluate their ability to act as inhibitors of these enzymes and to extend our ongoing antimalarial structure-activity relationship studies. In this series, (S)-3-hydroxy-2-(phosphonoethoxy)propyl (HPEP), (S)-2-(phosphonomethoxy)propanoic acid (CPME), or (S)-2-(phosphonoethoxy)propanoic acid (CPEE) are the acyclic moieties. Of this group, (S)-3-hydroxy-2-(phosphonoethoxy)propylguanine (HPEPG) exhibits the highest potency for PfHGXPRT, with a Ki value of 0.1 μM and a Ki value for human HGPRT of 0.6 μM. The crystal structures of HPEPG and HPEPHx (where Hx=hypoxanthine) in complex with human HGPRT were obtained, showing specific interactions with active site residues. Prodrugs for the HPEP and CPEE analogues were synthesized and tested for in vitro antimalarial activity. The lowest IC50 value (22 μM) in a chloroquine-resistant strain was observed for the bis-amidate prodrug of HPEPG.

• MeSH
• antimalarika chemická syntéza   chemie   farmakologie   MeSH
• hypoxanthinfosforibosyltransferasa antagonisté a inhibitory   metabolismus   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• nukleosidy chemická syntéza   chemie   farmakologie   MeSH
• organofosfonáty chemická syntéza   chemie   farmakologie   MeSH
• parazitické testy citlivosti MeSH
• Plasmodium falciparum účinky léků   enzymologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH