A5045905543- Receptor Mechanisms and Signaling
- Peptidase Inhibition and Analysis
- Cancer, Hypoxia, and Metabolism
- Chemical Synthesis and Analysis
- Histone Deacetylase Inhibitors Research
- Enzyme function and inhibition
- Radiopharmaceutical Chemistry and Applications
- Prostate Cancer Treatment and Research
- Mass Spectrometry Techniques and Applications
- Endoplasmic Reticulum Stress and Disease
- Computational Drug Discovery Methods
- Hormonal Regulation and Hypertension
- RNA Interference and Gene Delivery
- Eicosanoids and Hypertension Pharmacology
- Monoclonal and Polyclonal Antibodies Research
- Protein Structure and Dynamics
- Plant-based Medicinal Research
- Chromatography in Natural Products
- Lysosomal Storage Disorders Research
- Molecular Biology Techniques and Applications
- Nanopore and Nanochannel Transport Studies
- HIV/AIDS drug development and treatment
- Bacterial Infections and Vaccines
- Ubiquitin and proteasome pathways
- Glycosylation and Glycoproteins Research
Czech Academy of Sciences, Institute of Biotechnology
2018-2025
Czech Academy of Sciences
2020-2025
Charles University
2016-2022
Czech Academy of Sciences, Institute of Microbiology
2016
Tubastatin A, a tetrahydro-γ-carboline-capped selective HDAC6 inhibitor (HDAC6i), was rationally designed 10 years ago, and has become the best investigated HDAC6i to date. It shows efficacy in various neurological disease animal models, as plays crucial regulatory role axonal transport deficits, protein aggregation, well oxidative stress. In this work, we provide new insights into by investigating molecular basis of its interactions with through X-ray crystallography, determining functional...
Prostate-specific membrane antigen (PSMA) is a well-characterized tumor marker associated with prostate cancer and neovasculature of most solid tumors. PSMA-specific ligands are thus being developed to deliver imaging or therapeutic agents cells. Here, we report on crystal structure human PSMA in complex A9g, 43-bp RNA aptamer, that was determined the 2.2 Å resolution limit. The analysis PSMA/aptamer interface allows for identification key interactions critical nanomolar binding affinity...
PSMA-617 is recognized as a benchmark ligand for prostate-specific membrane antigen (PSMA) owing to its broad utilization in prostate cancer (PCa) targeted radionuclide therapy. In this study, the structure–activity relationships (SAR) of and two novel analogs featuring modified linkers were investigated. compounds P17 P18, 2-naphthyl-l-Ala moiety was replaced with less lipophilic 3-styryl-l-Ala while cyclohexyl ring P18 phenyl group. The first ever crystal structure PSMA/PSMA-617 complex...
Microtubules (MTs) undergo diverse post-translational modifications that regulate their structural and functional properties. Among these, polyglutamylation - a dominant conserved modification targeting the unstructured tubulin C-terminal tails plays pivotal role in defining code. Here, we uncovered novel mechanism by which tyrosine ligase-like 11 (TTLL11) expands diversifies Cryo-electron microscopy revealed unique bipartite MT recognition strategy wherein TTLL11 binding catalytic domains...
Histone deacetylase (HDAC) inhibitors used in the clinic typically contain a hydroxamate zinc-binding group (ZBG). However, more recent work has shown that use of alternative ZBGs, and, particular, heterocyclic oxadiazoles, can confer higher isoenzyme selectivity and favorable ADMET profiles. Herein, we report on synthesis biochemical, crystallographic, computational characterization series oxadiazole-based selectively targeting HDAC6 isoform. Surprisingly, but line with very finding...
In recent years, a number of drugs targeting the prostate-specific membrane antigen (PSMA) have become important tools in diagnosis and treatment prostate cancer. present work, we report on synthesis preclinical evaluation series 18F-labeled PSMA ligands for diagnostic application based theragnostic ligand PSMA-617. By applying modifications to linker structure, insight into structure-activity relationship could be gained, highlighting importance hydrophilicity stereoselectivity interaction...
The sulfonamide function is used extensively as a general building block in various inhibitory scaffolds and, more specifically, zinc-binding group (ZBG) of metalloenzyme inhibitors. Here, we provide biochemical, structural, and computational characterization metallopeptidase complex with inhibitors, where the mono- bisubstituted sulfamide functions are designed to directly engage zinc ions bimetallic enzyme site. Structural data showed that while monosubstituted sulfamides coordinate...
Prostate-specific membrane antigen (PSMA) is an excellent biomarker for the early diagnosis of prostate cancer progression and metastasis. The most promising PSMA-targeted agents in clinical phase are based on Lys–urea–Glu motif, which Lys Glu α-(l)-amino acids. In this study, we aimed to determine effect β- γ-amino acids S1 pocket binding affinity PSMA. We synthesized evaluated acid analogues with (S)- or (R)-configuration keeping α-(l)-Glu as S1′-binding pharmacophore. structure–activity...
The design and synthesis of prostate specific membrane antigen (PSMA) ligands derived from 2-aminoadipic acid, a building block that has not previously been used to construct PSMA ligands, are reported. effects both the linker length an N-substituent our were probed, X-ray structures five these bound obtained. Among disclosed herein, 13b showed highest inhibitory activity for PSMA. As ligand can readily be radiolabeled since its fluorine atom is adjacent nitrogen pyridine ring, use this...
Fonticins are phage tail-like bacteriocins produced by the Gram-negative bacterium Pragia fontium from family Budviciaceae. This produces contractile-type particles that adsorb on surface of sensitive bacteria and penetrate cell wall, probably during contraction, in a way similar to type VI secretion system. We characterized pore-forming activity fonticins using both living cells vitro model membranes. Using potassium leakage assay, we show able permeabilize cells. On black lipid membranes,...
Our previously reported HDAC6 inhibitor (HDAC6i) Marbostat-100 (4) has provided many arguments for further clinical evaluation. By the substitution of acidic hydrogen 4 different carbon residues, we were able to generate an all-carbon stereocenter, which significantly improves hydrolytic stability inhibitor. Further asymmetric synthesis shown that (S)-configured inhibitors preferentially bind HDAC6. This led highly selective and potent methyl-substituted derivative S-29b, elicited a...