A5024818475- HIV/AIDS drug development and treatment
- Synthesis and Characterization of Heterocyclic Compounds
- Biochemical and Molecular Research
- DNA and Nucleic Acid Chemistry
- Organophosphorus compounds synthesis
- Cytomegalovirus and herpesvirus research
- Carbohydrate Chemistry and Synthesis
- Fluorine in Organic Chemistry
- Herpesvirus Infections and Treatments
- Pneumocystis jirovecii pneumonia detection and treatment
- Epigenetics and DNA Methylation
- Virus-based gene therapy research
- Synthesis and Reactions of Organic Compounds
- Poxvirus research and outbreaks
- Neuroblastoma Research and Treatments
- Click Chemistry and Applications
- Neurofibromatosis and Schwannoma Cases
- Synthesis and Reactivity of Heterocycles
- Enzyme Catalysis and Immobilization
- Synthesis and biological activity
- Plant Virus Research Studies
- HIV Research and Treatment
- Synthesis and Reactivity of Sulfur-Containing Compounds
- Chemical Synthesis and Analysis
- Polyomavirus and related diseases
Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry
2016-2025
Czech Academy of Sciences
2008-2025
Rega Institute for Medical Research
2007
KU Leuven
2007
Osnabrück University
1991-1992
Research Institute for Pharmacy and Biochemistry (Czechia)
1991
Itaconate, an endogenous immunomodulator from the tricarboxylic acid (TCA) cycle, shows therapeutic effects in various disease models, but is highly polar with poor cellular permeability. We previously reported a novel, topical itaconate derivative, SCD-153, for treatment of alopecia areata. Here, we present discovery orally available derivatives systemic and skin disorders. Four sets prodrugs were synthesized using pivaloyloxymethyl (POM), isopropyloxycarbonyloxymethyl (POC),...
Treatment of 5-azacytosine sodium salt with diisopropyl [(2-chloroethoxy)methyl]phosphonate followed by removal ester groups BrSi(CH3)3 afforded 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (3). Reaction [(trityloxy)methyl]-(2S)-oxirane etherification (bromomethyl)phosphonate and gave 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (1). The synthesis 6-azacytosine congener 2 was analogous using N4-benzoylated intermediates. Compound 1 shown to exert strong activity against a broad...
Escherichia coli (Ec) cells possess two purine salvage enzymes: xanthine-guanine phosphoribosyltransferase (XGPRT) and hypoxanthine (HPRT). EcXGPRT shares a common structural feature with other members of this family, flexible loop that closes over the active site during catalysis. The replacement six these amino acids by alanine has no effect on Km for substrates. However, Ki nucleoside monophosphate increases 27-fold, kcat is reduced ∼200-fold. Nucleoside phosphonates (NP) are good...
Summary Repetitive DNA sequences and some genes are epigenetically repressed by transcriptional gene silencing (TGS). When genetic mutants not available or problematic to use, TGS can be suppressed chemical inhibitors. However, informed use of epigenetic inhibitors is partially hampered the absence any systematic comparison. In addition, there emerging evidence that cause genomic instability, but nature this damage its repair remain unclear. To bridge these gaps, we compared effects...
Despite the eradication of smallpox four decades ago, poxviruses continue to be a threat humans and animals. The arsenal anti-poxvirus agents is very limited understanding mechanisms resistance targeting viral DNA polymerases fundamental for development antiviral therapies. We describe here phenotypic genotypic characterization poxvirus polymerase mutants isolated under selective pressure with different acyclic nucleoside phosphonates, including HPMPC (cidofovir), cHPMPC, HPMPA, cHPMPA,...
Reaction of 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (1) with dicyclohexylcarbodiimide and N,N,-dicyclohexyl-4-morpholinocarboxamidine in dimethylformamide at elevated temperature afforded the corresponding cyclic phosphonate 2, that is, 1-{[(5S)-2-hydroxy-2-oxido-1,4,2-dioxaphosphinan-5-yl]methyl}-5-azacytosine. Compound 2 exerts strong vitro activity against DNA viruses, comparable parent compound 1. Transformation to its tetrabutylammonium salt followed by reaction alkyl...
Camelpox virus (CMLV) is the closest known to variola virus. Here we report on anti-CMLV activities of several acyclic nucleoside phosphonates (ANPs) related cidofovir [(S)-1-(3-hydroxy-2-phosphonomethoxypropyl)cytosine (HPMPC; Vistide)] against two CMLV strains, CML1 and CML14. Cytopathic effect (CPE) reduction assays performed with human embryonic lung fibroblast monolayers revealed selectivities first classes ANPs (cHPMPA, HPMPDAP, HPMPO-DAPy) hexadecyloxyethyl ester...
The acyclic nucleoside phosphonate (ANP) family of drugs shows promise as therapeutics for treating poxvirus infections. However, it has been questioned whether the utility these compounds could be compromised through intentional genetic modification viral sequences by bioterrorists or selection drug resistance viruses during course antiviral therapy. To address concerns, vaccinia virus (strain Lederle) was passaged 40 times in medium containing an escalating dose...
2-Phosphonomethylpentanedioic acid (1, 2-PMPA) is a potent inhibitor of glutamate carboxypeptidase II which has demonstrated robust neuroprotective efficacy in many neurological disease models. However, 1 highly polar containing phosphonate and two carboxylates, severely limiting its oral bioavailability. We strategized to mask the groups via prodrug approach, increasing likelihood passive absorption. Our initial strategy was cover with hydrophobic moieties such as pivaloyloxymethyl (POM)...
9-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) and its cyclic form were selected for further evaluation as potential drug candidates against poxvirus infections. To increase bioavailability of these compounds, synthesis their structurally diverse ester prodrugs was carried out: alkoxyalkyl (hexadecyloxypropyl, octadecyloxyethyl, hexadecyloxyethyl), pivaloyloxymethyl (POM), 2,2,2-trifluoroethyl, butylsalicylyl, based on peptidomimetics. Most HPMPDAP synthesized in...
Cidofovir or (S)-HPMPC is one of the three antiviral drugs that might be used for treatment orthopoxvirus infections. and its 2,6-diaminopurine counterpart, (S)-HPMPDAP, have been described to select, in vitro, drug resistance mutations viral DNA polymerase (E9L) gene vaccinia virus (VACV). Here, extend our knowledge development among orthopoxviruses, we selected, camelpox viruses (CMLV) resistant (S)-HPMPDAP identified a single amino acid change, T831I, double mutation, A314V+A684V, within...
Murine polyomavirus and simian virus 40 were used to evaluate the potencies of compounds three classes acyclic nucleoside phosphonates: (i) original HPMP (3-hydroxy-2-phosphonomethoxypropyl) PME (2-phosphonomethoxyethyl) derivatives, (ii) 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidine (DAPy) (iii) a new class derivatives containing 5-azacytosine moiety. The last showed highest activities selectivities against both polyomaviruses.
BK virus (BKV), a belonging to the polyomavirus family, is circular double-stranded DNA that causes nephropathies in immunocompromised patients after kidney or bone marrow transplantation. The occurrence of polyomavirus-associated nephropathy transplant may trigger graft loss, and guidelines for management BKV infection have not yet been clearly established. Treatment with cidofovir (CDV) {(S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC)}, an acyclic phosphonate analogue dCMP...
ABSTRACT Acyclic nucleoside phosphonates (ANPs), such as ( S )-1-[(3-hydroxy-2-phosphonomethoxy)propyl)]cytosine (HPMPC), are an important group of broad-spectrum antiviral agents with activity against DNA viruses. In this report, we present the in vitro potencies novel ANPs gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus (EBV), and three animal gammaherpesviruses. 1-( )-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (HPMP-5-azaC),...
Therminator is the hero when it comes to enzymatic production of phosphonomethyl–threosyl oligonucleotides with a non-natural 3′–2′ linkage (see scheme). The ability polymerase catalyze condensation diphosphate derivatives nucleosides give modified oligomers promises be quite general. Such are useful tools in synthetic biology because innate stability phosphonate linkage. Supporting information for this article available on WWW under...