A5019482739- Chromatin Remodeling and Cancer
- interferon and immune responses
- Mosquito-borne diseases and control
- Protein Degradation and Inhibitors
- Biochemical and Molecular Research
- Retinoids in leukemia and cellular processes
- RNA and protein synthesis mechanisms
- DNA and Nucleic Acid Chemistry
- Cytokine Signaling Pathways and Interactions
- Bacteriophages and microbial interactions
- Calcium signaling and nucleotide metabolism
- RNA modifications and cancer
- SARS-CoV-2 and COVID-19 Research
- Viral Infections and Immunology Research
- Viral Infections and Vectors
- Peptidase Inhibition and Analysis
- Synthesis and Biological Evaluation
- Adenosine and Purinergic Signaling
- Cellular transport and secretion
- Protein Tyrosine Phosphatases
- HIV Research and Treatment
- Click Chemistry and Applications
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- HIV/AIDS drug development and treatment
- Immune Response and Inflammation
Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry
2016-2025
Czech Academy of Sciences
2010-2025
Gilead Sciences (Australia)
2015
Ghent University
2010-2011
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19 pandemic. 2'-O-RNA methyltransferase (MTase) one enzymes this virus that a potential target for antiviral therapy as it crucial RNA cap formation; an essential process viral stability. This MTase function associated with nsp16 protein, which requires cofactor, nsp10, its proper activity. Here we show crystal structure nsp10-nsp16 complex bound to pan-MTase inhibitor sinefungin in active site. Our structural...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of disease 2019 (COVID-19). SARS-CoV-2 a single-stranded positive-sense RNA virus. Like other coronaviruses, has an unusually large genome that encodes four structural proteins and sixteen nonstructural proteins. The nucleocapsid phosphoprotein N essential for linking viral to membrane. Both N-terminal binding (N-NTD) C-terminal dimerization domains are involved in capturing and, intrinsically disordered...
Neutralizing antibodies that target the receptor-binding domain (RBD) of SARS-CoV-2 spike protein are among most promising approaches against COVID-191,2. A bispecific IgG1-like molecule (CoV-X2) has been developed on basis C121 and C135, two derived from donors who had recovered COVID-193. Here we show CoV-X2 simultaneously binds independent sites RBD and, unlike its parental antibodies, prevents detectable binding to cellular receptor virus, angiotensin-converting enzyme 2 (ACE2)....
There is growing evidence that Zika virus (ZIKV) can cause devastating infant brain defects and other neurological disorders in humans. However, no specific antiviral therapy available at present. We tested a series of 2′-C- or 2′-O-methyl–substituted nucleosides, 2′-C-fluoro-2′-C-methyl–substituted 3′-O-methyl–substituted 3′-deoxynucleosides, derivatives with 4′-C-azido substitution, heterobase-modified neplanocins for their ability to inhibit ZIKV replication cell culture. Antiviral...
Phosphatidylinositol 4-kinase beta (PI4KB) is one of four human PI4K enzymes that generate phosphatidylinositol 4-phosphate (PI4P), a minor but essential regulatory lipid found in all eukaryotic cells. To convert their substrates, PI4Ks must be recruited to the correct membrane compartment. PI4KB critical for maintenance Golgi and trans network (TGN) PI4P pools, however, actual targeting mechanism TGN membranes unknown. Here, we present an NMR structure complex its interacting partner,...
In this study, we have focused on the structure-based design of inhibitors one two SARS-CoV-2 methyltransferases (MTases), nsp14. This MTase catalyzes transfer methyl group from S-adenosyl-l-methionine (SAM) to cap guanosine triphosphate moiety newly synthesized viral RNA, yielding methylated capped RNA and S-adenosyl-l-homocysteine (SAH). As crystal structure nsp14 is unknown, taken advantage its high homology SARS-CoV prepared model, which has allowed us identify novel SAH derivatives...
Monkeypox is a disease with pandemic potential. It caused by the monkeypox virus (MPXV), double-stranded DNA from Poxviridae family, that replicates in cytoplasm and must encode for its own RNA processing machinery including capping machinery. Here, we present crystal structures of 2'-O-RNA methyltransferase (MTase) VP39 complex pan-MTase inhibitor sinefungin series inhibitors were discovered based on it. A comparison this MTase enzymes unrelated single-stranded viruses (SARS-CoV-2 Zika)...
Abstract In acute myeloid leukemia (AML), SWI/SNF chromatin remodeling complexes sustain leukemic identity by driving high levels of MYC. Previous studies have implicated the hematopoietic transcription factor PU.1 (SPI1) as an important target inhibition, but is widely regarded to pioneer-like activity. As a result, many questions remained regarding interplay between and in AML well normal hematopoiesis. Here we found that binds most its targets SWI/SNF-independent manner recruits promote...
Tick-borne encephalitis virus (TBEV) is a leading cause of human neuroinfections in Europe and Northeast Asia. There are no antiviral therapies for treating TBEV infection. A series nucleoside analogues was tested the ability to inhibit replication porcine kidney cells neuroblastoma cells. The interactions three with viral polymerase were simulated using advanced computational methods. 7-deaza-2'-C-methyladenosine (7-deaza-2'-CMA), 2'-C-methyladenosine (2'-CMA), 2'-C-methylcytidine (2'-CMC)...
Cyclic dinucleotides are second messengers in the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway, which plays an important role recognizing tumor cells and viral or bacterial infections. They bind to STING adaptor protein trigger expression cytokines via TANK binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) inhibitor nuclear factor-κB (IκB) (IKK)/nuclear (NFκB) signaling cascades. In this work, we describe enzymatic preparation 2′–5′,3′–5′-cyclic...
Coronaviral methyltransferases (MTases), nsp10/16 and nsp14, catalyze the last two steps of viral RNA-cap creation that takes place in cytoplasm. This cap is essential for stability RNA and, most importantly, evasion innate immune system. Non-capped recognized by immunity which leads to its degradation activation antiviral immunity. As a result, both coronaviral MTases are center scientific scrutiny. Recently, X-ray cryo-EM structures enzymes were solved even complex with other parts...
Phosphatidylinositol 4-kinase IIIβ (PI4KB) is indispensable for the replication of various positive-sense single stranded RNA viruses, which hijack this cellular enzyme to remodel intracellular membranes infected cells set up functional machinery. Therefore, inhibition PI4K isoform leads arrest viral replication. Here, we report on synthesis novel PI4KB inhibitors, were rationally designed based two distinct structural types inhibitors that bind in ATP binding side PI4KB. These "hybrids" not...
Phosphatidylinositol 4-kinase IIIβ is a cellular lipid kinase pivotal to pathogenesis of various RNA viruses. These viruses hijack the enzyme in order modify structure intracellular membranes and use them for construction functional replication machinery. Selective inhibitors this are potential broad-spectrum antiviral agents, as inhibition results arrest PI4K IIIβ-dependent Herein, we report detailed study novel selective IIIβ, which exert activity against panel single-stranded...
Cyclic dinucleotides (CDNs) are second messengers that bind to the stimulator of interferon genes (STING) and trigger expression type I interferons proinflammatory cytokines. Here we evaluate activity 3′,3′-c-di(2′F,2′dAMP) its phosphorothioate analogues against five STING allelic forms in reporter-cell-based assays rationalize our findings with X-ray crystallography quantum mechanics/molecular mechanics calculations. We show presence fluorine 2′ position improves not only wild (WT) but also...
Untargeted analysis based on high-resolution mass spectrometry is a key tool in clinical metabolomics, natural product discovery, and exposomics, with compound identification remaining the major bottleneck. Currently, MS2 fragmentation data spectral library matching are standard workflow for confident annotation. Multi-stage (MSn) yields more profound insights into substructures, enabling validation of pathways; however, community lacks open MSn reference compounds. Here, we describe...