Ivona Hančlová's research while affiliated with The Czech Academy of Sciences and other places

Publications (8)

Article
Full-text available
Apart from its role in insulin receptor (IR) activation, the C terminus of the B-chain of insulin is also responsible for the formation of insulin dimers. The dimerization of insulin plays an important role in the endogenous delivery of the hormone and in the administration of insulin to patients. Here, we investigated insulin analogues with select...
Article
Full-text available
Apart from its role in insulin receptor (IR) activation, the C terminus of the B-chain of insulin is also responsible for the formation of insulin dimers. The dimerization of insulin plays an important role in the endogenous delivery of the hormone and in the administration of insulin to patients. Here, we investigated insulin analogues with select...
Article
In the present work, we describe in detail an efficient solution synthesis of norleucine-derived phosphonopeptides mimicking the peptide sequences Nle-Gly(Ala) and Nle-Gly(Ala)-Val. The most efficient strategy involved use of the benzyl group. The synthesis was achieved through BOP-catalysed coupling of the monobenzyl ester of the N-Cbz-protected p...
Article
Betaine-homocysteine S-methyltransferase (BHMT) catalyzes the transfer of a methyl group from betaine to l-homocysteine, yielding dimethylglycine and l-methionine. In this study, we prepared a new series of BHMT inhibitors. The inhibitors were designed to mimic the hypothetical transition state of BHMT substrates and consisted of analogues with NH,...
Article
Full-text available
We present herein a straightforward synthesis of N-Fmoc-protected synthons derived from a phosphinic analogue of methionine. These precursors were used successfully for the solid-phase synthesis of methionine-mimic phosphinopeptides using BOP-catalyzed coupling without protection of the phosphoryl moiety. We also prepared a new type of pseudopeptid...
Article
In this study, we prepared several shortened and full-length insulin analogues with substitutions at position B26. We compared the binding affinities of the analogues for rat adipose membranes with their ability to lower the plasma glucose level in nondiabetic Wistar rats in vivo after subcutaneous administration, and also with their ability to sti...
Article
In this paper, we present the detailed synthetic protocol and characterization of Fmoc-Lys(Pac)-OH, its use for the preparation of octapeptides H-Gly-Phe-Tyr-N-MePhe-Thr-Lys(Pac)-Pro-Thr-OH and H-Gly-Phe-Phe-His-Thr-Pro-Lys(Pac)-Thr-OH by solid-phase synthesis, trypsin-catalyzed condensation of these octapeptides with desoctapeptide(B23-B30)-insuli...

Citations

... To prepare an antigen to induce monoclonal catalytic antibodies capable of catalyzing peptide-bond formation reactions, the phosphonodepsidipeptide 39 was synthesized via the coupling of the hydroxy analog of tryptophan amide with 4-nitrobenzyl (R)-N-Fmoc 1-amino(cyclohexyl)methylphosphonochloridate (38), which was prepared from diethyl (R)-N-Fmoc 1-amino(cyclohexyl)methylphosphonate (36) via a selective basic hydrolysis, chlorination, esterification with 4-nitrobenzyl alcohol, selective basic hydrolysis, and chlorination. After the treatment of compound 39 with piperidine, the N-terminal free dipeptide was obtained and acylated with hexanedioic anhydride to afford the designed hapten 40 (Scheme 7) [11]. ...
... Methods for the synthesis of phosphonic and phosphonous methionine analogues are based on the use of methylthiopropionic aldehyde [5] or its oxime [10,11]. In this work we used previously synthesized N,N'methylthiopropylidenebis(benzylcarbamate) 2 for amidoalkylation of phosphonous acid 3 containing structural isosteres of glutamic acid, since an attempt to carry out amidoalkylation of acid 3 using benzylcarbamate and methylthiopropionic aldehyde in accordance with the three-component amide version of the Kabachnik-Fields reaction failed. ...
... Unfortunately, the majority of studies in the literature, especially those reporting in vitro cell culture experiments, have used insulin concentrations that are many times higher than those found physiologically, confounding interpretation of these studies and clouding the field. Insulin binds to its receptor tyrosine kinase, insulin receptor (INSR) with an IC50 of 0.89 nM and to the growth factor 1 receptor (IGF1R) with an IC50 of 30 to 400 nM [35][36][37]. INSR/IGF1R can form heterodimer hybrid receptors that have a higher affinity for IGF1 than insulin [38][39][40]. Binding to the INSR and related receptors leads to tyrosine kinase autophosphorylation and binding of adapter proteins, called insulin receptor substrates (IRS1, IRS2, IRS3, IRS4), which attract the lipid kinase, phosphoinositide 3-kinase (PI3K). ...
... Dimerization data exists only for wild type, GF 9, GF 10, and GF 13, and thus comparisons between experimental and computational data proved challenging. We focused only on residues GlyB23-TyrB26 because these are the dimer interface residues that form backbone hydrogen bonds with another insulin monomer (Fig. 2B) [41,74,75]. ...
... In humans, a second enzyme catalyzes the methylation of homocysteine to generate methionine: betaine homocysteine methyltransferase. This enzyme uses betaine (trimethylglycine) as methyl donor, yielding methionine and dimethylglycine (Figs. 4, 5) (Holme and Ronge 1989;Vanek et al. 2009). Betaine is a nutrient obtained from dietary food. ...
... 4,7 2) Trypsin-mediated ligation using desoctapeptide (B23-30) insulin (DOI) suffers from low conversion rates ( Figure 1A). 8,[16][17][18][19] Our group recently reported sortase A-mediated ligation with a high conversion rate (Figure 1B). 20 However, it can only conjugate peptide substrates after the C-terminus of the B chain. ...
... However, by introducing the Q18Y change and concomitantly strengthening the interaction at the FnIII-1' , as is seen with the sextuple IGF-II analogue, signalling potency can be increased to equal that of insulin 17 . Other residues that contact the L1 alone, including SB9, EB21 and YB26 (YB26 shown in Fig. 7), also don't contribute greatly to IR binding affinity or biological activity 46,51,52 , supporting the proposal that an L1 only interaction has a lesser impact on activation than the interactions with the αCT' and FnIII-1' domains of the opposite monomer. In conclusion, our findings provide some insight into the mechanism of IR activation enabled through specific ligand:receptor interactions. ...