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Phenotypic drug resistance investigation of various clinical HIV-1 genotypes KU Leuven
Since the mid-nineties, the repertoire of antiv iral drugs for the treatment of human immunodefici ency virus type 1 (HIV-1) has diversified substant ially enabling the prescription of highly active a ntiviral therapy, even in patients who have failed multiple antiretroviral regimens. Despite th e potency of current antiviral drugs, therapy fail ures do occur. Viral replication in the prese nce of ART results into the generation and se lection ...
Sulfonate derived phosphoramidates as active intermediates in the enzymatic primer-extension of DNA KU Leuven
Novel unnatural 5'-phosphoramidate nucleosides, capable of being processed as substrates by DNA polymerases for multiple nucleotide incorporations, have been designed. The mimics feature metabolites such as taurine and a broad range of aliphatic sulfonates coupled through a P-N bond to the 5'-phosphate position of deoxynucleotides, to allow binding interactions in the enzyme active site. The utility of all of the analogues as pyrophosphate ...
Prediction of drug response from genetic sequence data using regression techniques KU Leuven
Regression techniques are increasingly important as automatic methods to study complex high-dimensional biological systems and to separate true signal from experimental noise.In this thesis, we developed novel methodologies to build linear regression models with low complexity that are at the same time accurate to predict drug response (phenotype) from HIV-1 genetic sequence mutations (genotype), where the choice of methodology depended on the ...
Covalently locking nucleic acid structures by the inducible furan cross-linking strategy: new application Universiteit Gent
Towards DNA based esterases: uncovering Hoogsteen face regulation of the pKaH of a tethered imidazole functionality by NMR and molecular dynamics Universiteit Gent
Chemical fidelity of an RNA polymerase ribozyme KU Leuven
The emergence of catalytically active RNA enzymes (ribozymes) is widely believed to have been an important transition in the origin of life. In the context of a likely heterogeneous chemical environment, substrate specificity and selectivity of these primordial enzymes would have been critical for function. Here we have explored the chemical fidelity, i.e. substrate selectivity and specificity for both single and multiple catalytic steps of the ...
Combinational therapies for HIV: a focus on EVG/COBI/FTC/TDF KU Leuven
Introduction: The co-formulation of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) is a new, investigational, once-daily (q.d.) drug, currently undergoing Phase II and III clinical trials. Next to the nucleotide/nucleoside reverse transcriptase inhibitors FTC and TDF, it contains EVG, the second member of the HIV-1 integrase strand transfer inhibitor class, together with its pharmacokinetic booster COBI. ...
Synthesis of Novel AZA-Analogues of Tiazofurin with 2-[5,5-bis(Hydroxymethyl)Pyrrolidin-2-yl] Framework as Sugar Mimic KU Leuven
The novel aza-analogues of tiazofurin (TZF) with 2-[5,5-bis(hydroxymethyl)pyrrolidin-2-yl] moiety, as sugar mimic, were synthesized from O,O-cyclohexylidene derivative of 4,4-bis(hydroxymethyl)-4-nitrobutanal in multi-gram scale. The synthetic route consisted of three stages: (i) the synthesis of corresponding derivative of 5,5-bis(hydroxymethyl)pyrrolidine-2-carbonitrile, (ii) the construction of ethyl thiazole-2-carboxylate part by the ...
Synthesis of Novel AZA-Analogues of Tiazofurin with 2-[5,5-bis(Hydroxymethyl)Pyrrolidin-2-yl] Framework as Sugar Mimic KU Leuven
The novel aza-analogues of tiazofurin (TZF) with 2-[5,5-bis(hydroxymethyl)pyrrolidin-2-yl] moiety, as sugar mimic, were synthesized from O,O-cyclohexylidene derivative of 4,4-bis(hydroxymethyl)-4-nitrobutanal in multi-gram scale. The synthetic route consisted of three stages: (i) the synthesis of corresponding derivative of 5,5-bis(hydroxymethyl)pyrrolidine-2-carbonitrile, (ii) the construction of ethyl thiazole-2-carboxylate part by the ...