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View article: Exploring advanced methodologies for NS5 methyltransferase targeted drug discovery
Exploring advanced methodologies for NS5 methyltransferase targeted drug discovery Open
Emerging viral pathogens highlight the need for targeted antiviral strategies, particularly against mechanistically validated enzymes like the Dengue virus NS5 methyltransferase - an essential component of viral RNA capping and immune evas…
View article: Mechanistic insights into alcohol-induced DNA crosslink repair by Slx4-Xpf-Ercc1 nuclease complex in the Fanconi anaemia pathway
Mechanistic insights into alcohol-induced DNA crosslink repair by Slx4-Xpf-Ercc1 nuclease complex in the Fanconi anaemia pathway Open
Alcohol is broken down in the body into acetaldehyde, a toxic chemical that can damage DNA by creating interstrand crosslinks (AA-ICL). These crosslinks block DNA replication and threaten the stability of the genome. A rare genetic disease…
View article: A recombinant expression system for the <i>Plasmodium falciparum</i> proteasome enables structural analysis of its assembly and the design of selective inhibitors
A recombinant expression system for the <i>Plasmodium falciparum</i> proteasome enables structural analysis of its assembly and the design of selective inhibitors Open
The Plasmodium falciparum 20S proteasome (Pf20S) has emerged as a promising antimalarial target. Development of therapeutics to this target has previously relied on native purifications of Pf20S, which is challenging and has limited the sc…
View article: Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome
Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome Open
The 20S proteasome, a critical component of the ubiquitin–proteasome system, plays a central role in regulating protein degradation in eukaryotic cells. Marizomib (MZB), also known as salinosporamide A, is a natural γ-lactam-β-lactone comp…
View article: Structural insights into Salinosporamide A mediated inhibition of the human 20S proteasome
Structural insights into Salinosporamide A mediated inhibition of the human 20S proteasome Open
The 20S proteasome, a critical component of the ubiquitin-proteasome system, plays a central role in regulating protein degradation in eukaryotic cells. Marizomib (MZB), a natural γ-lactam-β-lactone compound derived from Salinispora tropic…
View article: SPR is a fast and straightforward method to estimate the binding constants of cyclic dinucleotides to their binding partners, such as STING or poxin
SPR is a fast and straightforward method to estimate the binding constants of cyclic dinucleotides to their binding partners, such as STING or poxin Open
The development of small molecule drugs that target protein binders is the central goal in medicinal chemistry. During the lead compound development process, hundreds or even thousands of compounds are synthesized, with the primary focus o…
View article: Enzymatic synthesis of reactive RNA probes containing squaramate-linked cytidine or adenosine for bioconjugations and cross-linking with lysine-containing peptides and proteins
Enzymatic synthesis of reactive RNA probes containing squaramate-linked cytidine or adenosine for bioconjugations and cross-linking with lysine-containing peptides and proteins Open
Protein-RNA interactions play important biological roles and hence reactive RNA probes for cross-linking with proteins are important tools in their identification and study. To this end, we designed and synthesized 5′- O -triphosphates bea…
View article: Distinct substrate specificities of the three catalytic subunits of the <i>Trichomonas vaginalis</i> proteasome
Distinct substrate specificities of the three catalytic subunits of the <i>Trichomonas vaginalis</i> proteasome Open
The protozoan parasite Trichomonas vaginalis (Tv) causes trichomoniasis, the most common non‐viral sexually transmitted infection in the world. Although Tv has been linked to significant health complications, only two closely related 5‐nit…
View article: Evaluating Antimalarial Proteasome Inhibitors for Efficacy in <i>Babesia</i> Blood Stage Cultures
Evaluating Antimalarial Proteasome Inhibitors for Efficacy in <i>Babesia</i> Blood Stage Cultures Open
Tick-transmitted Babesia are a major global veterinary threat and an emerging risk to humans. Unlike their Plasmodium relatives, these erythrocyte-infecting Apicomplexa have been largely overlooked and lack specific treatment. Selective ta…
View article: Mechanistic Insights into Alcohol-Induced DNA Crosslink Repair by the Fanconi Anemia Nuclease Slx4-Xpf-Ercc1
Mechanistic Insights into Alcohol-Induced DNA Crosslink Repair by the Fanconi Anemia Nuclease Slx4-Xpf-Ercc1 Open
During cell division, DNA replication stalls upon alcohol-derived interstrand crosslink, employing DNA repair pathways. Acetaldehyde, a toxic metabolite of alcohol, can induce DNA crosslinks between complementary DNA strands, causing signi…
View article: Structural elucidation of recombinant Trichomonas vaginalis 20S proteasome bound to covalent inhibitors
Structural elucidation of recombinant Trichomonas vaginalis 20S proteasome bound to covalent inhibitors Open
The proteasome is a proteolytic enzyme complex essential for protein homeostasis in mammalian cells and protozoan parasites like Trichomonas vaginalis (Tv) , the cause of the most common, non-viral sexually transmitted disease. Tv and othe…
View article: Enzymatic Synthesis of Reactive RNA Probes Containing Squaramate-Linked Cytidine for Bioconjugations and Cross-Linking with Lysine-Containing Peptides and Proteins
Enzymatic Synthesis of Reactive RNA Probes Containing Squaramate-Linked Cytidine for Bioconjugations and Cross-Linking with Lysine-Containing Peptides and Proteins Open
We designed and synthesized cytidine 5′-O-triphosphate bearing a reactive squaramate group attached to position 5 of pyrimidine (CESQTP) and used it as substrate for polymerase synthesis of modified RNA. In vitro transcription with T7 RNA …
View article: Structure of SARS-CoV-2 MTase nsp14 with the inhibitor STM957 reveals inhibition mechanism that is shared with a poxviral MTase VP39
Structure of SARS-CoV-2 MTase nsp14 with the inhibitor STM957 reveals inhibition mechanism that is shared with a poxviral MTase VP39 Open
Nsp14 is an RNA methyltransferase (MTase) encoded by all coronaviruses. In fact, many viral families, including DNA viruses, encode MTases that catalyze the methylation of the RNA precap structure, resulting in fully capped viral RNA. This…
View article: Structural and functional insights in flavivirus NS5 proteins gained by the structure of Ntaya virus polymerase and methyltransferase
Structural and functional insights in flavivirus NS5 proteins gained by the structure of Ntaya virus polymerase and methyltransferase Open
Flaviviruses are single-stranded positive-sense RNA (+RNA) viruses that are responsible for several (re)emerging diseases such as yellow, dengue, or West Nile fevers. The Zika epidemic highlighted their dangerousness when a relatively beni…
View article: Novel analogues of a nonnucleoside SARS-CoV-2 RdRp inhibitor as potential antivirotics
Novel analogues of a nonnucleoside SARS-CoV-2 RdRp inhibitor as potential antivirotics Open
The RNA-dependent RNA polymerase (RdRp) represents a prominent target in the discovery and development of new antivirotics against RNA viruses, inhibiting the replication process. One of the most targeted RNA viruses of the last years is, …
View article: Abstract 2365 Class I phosphatidylinositol transfer proteins control organelle membrane lipid composition beyond supporting phosphoinositides synthesis
Abstract 2365 Class I phosphatidylinositol transfer proteins control organelle membrane lipid composition beyond supporting phosphoinositides synthesis Open
Phosphatidylinositol (PI) is one of the structural phospholipids in cellular membranes and serves as the substrate to form the seven phosphorylated inositol lipid species, collectively called phosphoinositides (PPIns). PPIns have been know…
View article: Fluorinated cGAMP analogs, which act as STING agonists and are not cleavable by poxins: Structural basis of their function
Fluorinated cGAMP analogs, which act as STING agonists and are not cleavable by poxins: Structural basis of their function Open
The cGAS-STING pathway is a crucial part of innate immunity; it serves to detect DNA in the cytoplasm and to defend against certain cancers, viruses, and bacteria. We designed and synthesized fluorinated carbocyclic cGAMP analogs, MD1203 a…
View article: Application of established computational techniques to identify potential SARS-CoV-2 Nsp14-MTase inhibitors in low data regimes
Application of established computational techniques to identify potential SARS-CoV-2 Nsp14-MTase inhibitors in low data regimes Open
Workflow used for identifying inhibitors of the SARS-CoV-2 non-structural protein 14 (nsp14), a key player in viral RNA methylation.
View article: Discovery of highly potent SARS-CoV-2 nsp14 methyltransferase inhibitors based on adenosine 5′-carboxamides
Discovery of highly potent SARS-CoV-2 nsp14 methyltransferase inhibitors based on adenosine 5′-carboxamides Open
SARS-CoV-2 nsp14 methyltransferase inhibitors based on adenosine 5′-carboxamides.
View article: Structural Biology in Antiviral Research – A Story Illustrated by the Tales of Lipid Kinases, STING and Viral Methyltransferases
Structural Biology in Antiviral Research – A Story Illustrated by the Tales of Lipid Kinases, STING and Viral Methyltransferases Open
This article focuses on the role of structural biology in the development of small molecules that serve as protein ligands, which could potentially be used as drugs in the future. Experimental methods are utilized to obtain structural info…
View article: Drug Discovery in Low Data Regimes: Leveraging a Computational Pipeline for the Discovery of Novel SARS-CoV-2 Nsp14-MTase Inhibitors
Drug Discovery in Low Data Regimes: Leveraging a Computational Pipeline for the Discovery of Novel SARS-CoV-2 Nsp14-MTase Inhibitors Open
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to significant global morbidity and mortality. A crucial viral protein, the non-structural protein 14 (nsp14), catalyzes the methylation of viral RNA and plays a critical role …
View article: Inhibitors of mpox VP39 2′-O methyltransferase efficiently inhibit the monkeypox virus
Inhibitors of mpox VP39 2′-O methyltransferase efficiently inhibit the monkeypox virus Open
The RNA 2'-O methyltransferase (MTase) VP39 of the monkeypox virus (MpxV) participates in RNA capping within poxviruses. Sub-micromolar inhibitors targeting this enzyme were already reported. However, these 7-deaza analogs of S-adenosyl me…
View article: Fluorinated cGAMP analogs, which act as STING agonists and are not cleavable by poxins: structural basis of their function
Fluorinated cGAMP analogs, which act as STING agonists and are not cleavable by poxins: structural basis of their function Open
The Stimulator of Interferon Genes (STING) plays a crucial role in the cGAS-STING pathway of innate immunity, detecting DNA in the cytoplasm and defending against certain cancers, viruses, and bacteria. We designed and synthesized fluorina…
View article: Structural elucidation of recombinant<i>Trichomonas vaginalis</i>20S proteasome bound to covalent inhibitors
Structural elucidation of recombinant<i>Trichomonas vaginalis</i>20S proteasome bound to covalent inhibitors Open
Proteasomes are essential for protein homeostasis in mammalian cells 1-4 and in protozoan parasites such as Trichomonas vaginalis (Tv) . 5 Tv and other protozoan 20S proteasomes have been validated as druggable targets. 6-8 However, in the…