A5004481123- Pancreatic function and diabetes
- Chemical Synthesis and Analysis
- Metabolism, Diabetes, and Cancer
- Growth Hormone and Insulin-like Growth Factors
- Click Chemistry and Applications
- Peptidase Inhibition and Analysis
- Folate and B Vitamins Research
- Biochemical and Molecular Research
- Protein Structure and Dynamics
- Diabetes and associated disorders
- Organophosphorus compounds synthesis
- Analytical Chemistry and Chromatography
- Microfluidic and Capillary Electrophoresis Applications
- Advanced biosensing and bioanalysis techniques
- Diabetes Management and Research
- RNA modifications and cancer
- Protease and Inhibitor Mechanisms
- Cancer, Hypoxia, and Metabolism
- Neuropeptides and Animal Physiology
- Enzyme Structure and Function
- Monoclonal and Polyclonal Antibodies Research
- Metabolism and Genetic Disorders
- Diabetes Treatment and Management
- Glycosylation and Glycoproteins Research
- Epigenetics and DNA Methylation
Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry
2016-2025
Czech Academy of Sciences
2004-2023
Chestnut Hill College
2021
University of York
2012
Charles University
1990-2009
University of Michigan
2004-2009
University of Illinois Urbana-Champaign
2004-2006
Commissariat à l'Énergie Atomique et aux Énergies Alternatives
1995-1999
National and Kapodistrian University of Athens
1996-1999
Collège de France
1999
The human somatic angiotensin converting enzyme (ACE) contains two homologous domains, each bearing a zinc-dependent active site. All of the synthetic inhibitors this used in clinical applications interact with these sites to similar extent. Recently, several lines evidence have suggested that N-terminal site ACE might be involved specific hydrolysis some important physiological substrates, like Acetyl-Seryl-Aspartyl-Lysyl-Proline, negative regulator hematopoietic stem cell differentiation...
Abstract Background Insects have an efficient self-defense system that is based on innate immunity. Recent findings disclosed many parallels between human and insect immunity, simultaneously fine differences in the processes various species been revealed. Studies immune systems of may uncover their host defense strategies. Results We analyzed proteomes hemocytes fat bodies Sarcophaga bullata larvae after infection by Escherichia coli . The 2-DE gels infected were compared with those...
The insulin receptor isoform A (IR-A) binds both and insulin-like growth factor (IGF)-II, although the affinity for IGF-II is 3–10-fold lower than depending on a cell tissue context. Notably, in mouse embryonic fibroblasts lacking IGF-IR expressing solely IR-A (R−/IR-A), more potent mitogen insulin. As endocytosis degradation provide spatial temporal regulation of signaling events, we hypothesized that could affect biological responses by differentially regulating trafficking. Using R−/IR-A...
The insulin/IGF superfamily is conserved across vertebrates and invertebrates. Our team has identified five viruses containing genes encoding viral insulin/IGF-1 like peptides (VILPs) closely resembling human insulin IGF-1. This study aims to characterize the impact of Mandarin fish ranavirus (MFRV) Lymphocystis disease virus-Sa (LCDV-Sa) VILPs on system for first time. We chemically synthesized single chain (sc, IGF-1 like) double (dc, forms MFRV LCDV-Sa VILPs. Using cell lines...
Several hundred phosphinic peptides having the general formula Z-(L,D)Pheψ(PO2CH2)(L,D)Xaa'-Yaa'-Zaa', where Xaa' = Gly or Ala and Yaa' Zaa' represent 20 different amino acids, have been synthesized by combinatorial chemistry approach. Peptide mixtures individual were evaluated for their ability to inhibit rat brain zinc endopeptidases 24-15 24-16. Numerous of this series act as potent (Ki in nanomolar range) mixed inhibitors these two peptidases. However, our systematic comparative strategy...
A new systematic approach, based on combinatorial chemistry of phosphinic peptides, is proposed for rapid development highly potent and selective inhibitors zinc metalloproteases. This strategy first evaluates the effects inhibitory potency selectivity following parameters: 1) size 2) position bond in sequence, 3) state (free or blocked) peptide extremities. After this selection step, influence inhibitor sequence analyzed order to determine identity residues that optimized both selectivity....
To develop solid-phase synthesis of phosphinic peptides, different FmocXaaPsi{PO(OAd)CH(2)}XaaOH building blocks have been prepared, where Fmoc is (fluorenylmethoxy)carbonyl. In this respect, the protection hydroxyphosphinyl function in these dipeptides by adamantyl group turns out to be convenient. The esters are completely stable basic conditions and can removed under relatively mild acidic conditions. Using blocks, despite bulkiness group, no particular problem coupling was observed...
Insulin is a key hormone in glucose homeostasis. Its lack causes severe health complications and has to be compensated by regular administration of insulin. Despite intense long-lasting research, more stable substitute yet discovered alleviate patients' issues. Here we report the development novel assay for screening potential insulin analogues based on recently published method DIANA. Our meets need fast, non-radioactive as sensitive alternative commonly used radioactive immunoassay.
Diabetes requires precise insulin management to maintain glycemic control and prevent severe complications. Glucose-responsive delivery systems envision an autonomous approach improve therapy. Here, a glucose-sensitive system comprising hyaluronic acid conjugated with diboronate glucose binder as carrier for diol-modified is shown. This seeks improved precision in delivery, leveraging bidentate binding achieve enhanced affinity specificity. Modification of diol motif preserves its native...
Insulin is a key protein hormone that regulates blood glucose levels and, thus, has widespread impact on lipid and metabolism. action manifested through binding of its monomeric form to the Receptor (IR). At present, however, our knowledge about structural behavior insulin based upon inactive, multimeric, storage-like states. The active structure, when in complex with receptor, must be different as residues crucial for interactions are buried within multimeric forms. Although exact nature...
Despite the recent first structural insight into insulin-insulin receptor complex, role of C terminus B-chain insulin in this assembly remains unresolved. Previous studies have suggested that part must rearrange to reveal amino acids crucial for interaction with receptor. The invariant Phe(B24), one key residues hormone, process unclear. For example, B24 site functionally tolerates substitutions D-amino but not L-amino acids. Here, we prepared and characterized a series B24-modified...
The N-terminus of the B-chain insulin may adopt two alternative conformations designated as T- and R-states. Despite recent structural insight into insulin–insulin receptor (IR) complexes, physiological relevance T/R transition is still unclear. Hence, this study focused on rational design, synthesis, characterization human analogues structurally locked in expected R- or T-states. Sites B3, B5, B8, capable affecting conformation B-chain, were subjects substitutions with amino acids specific...
The oligomeric state of the storage form human insulin in pancreas, which may be affected by several endogenous components β-cell granules such as arginine, is not known. Here, effect arginine on oligomerization investigated independently protein crystallography, molecular dynamics simulations, and capillary electrophoresis. combined results point to a strong ionic strength assembly. Molecular simulations electrophoretic measurements at low/mM salt concentrations show no significant...
The insulin receptor (IR, with its isoforms IR-A and IR-B) the insulin-like growth factor 1 (IGF-1R) are related tyrosine kinase receptors. Recently, portfolio of solved hormone-receptor structures has grown extensively thanks to advancements in cryo-electron microscopy. However, dynamics how these receptors transition between their inactive active state yet be fully understood. C-terminal part alpha subunit (αCT) is indispensable for formation hormone-binding site. We mutated αCT residues...
Abstract The management of diabetes in a manner offering autonomous insulin therapy responsive to glucose‐directed need, and moreover with dosing schedule amenable facile administration, remains an ongoing goal improve the standard care. While basal insulins reduced frequency, even once‐weekly are on horizon, there is still no approved that offers glucose‐responsive function. Herein, nanoscale complex combining both electrostatic‐ dynamic‐covalent interactions between synthetic dendrimer...
The insulin gene mutation c.137G>A (R46Q), which changes an arginine at the B22 position of mature hormone to glutamine, causes monogenic diabetes variant maturity-onset young (MODY). In MODY patients, this is heterozygous, and both mutant wild-type (WT) human are produced simultaneously. However, patients often depend on administration exogenous insulin. study, we chemically synthesized [GlnB22]-insulin characterized its biological structural properties. chemical synthesis analogue revealed...
The structural characterization of the insulin-insulin receptor (IR) interaction still lacks conformation crucial B21-B30 insulin region, which must be different from that in its storage forms to ensure effective binding. Here, it is shown analogues modified by natural amino acids at TyrB26 site can represent an active form this hormone. In particular, [AsnB26]-insulin and [GlyB26]-insulin attain a B26-turn-like differs all known structures native It also matches interface, avoiding...
Abstract We describe the synthesis of a trifunctional scaffold constructed from planar core trimesic acid derivatized with three propargylamine moieties. The was attached to solid‐phase resin through carboxylic group fluorinated alkyl spacer arm. orthogonal protection two alkyne groups triethylsilyl and triisopropylsilyl moieties enabled modular efficient derivatization different azides by using on amphiphilic ChemMatrix resin. showed that fluorine label can be used quantify content...