Biomedical subjects
Publications and source records attributed to Jaroslav Sebestík.
Described is a computer-assisted rational design of a DNA-bis-intercalator peptide library. The peptide library of 250 members was prepared and the most powerful binder identified. A value of the binding constant is almost two orders of magnitude higher than that of starting building block-9-aminoacridine. The binder affinity found toward calf thymus DNA is 30-fold of that of human prion peptide 106-126.
The finding that several derivatives of 9-aminoacridine were deacridinylated in the presence of primary aliphatic amines during the solid phase synthesis of acridine-peptide conjugates prompted us to investigate the acridin-9-yl moiety transfer from a relatively low-molecular acridine source to a high-molecular carrier. The hydrophobic polymer was used as a model of hydrophobic core of biologically active proteins. While the alpha-amino group in the peptide was found to play the role of weak acridine acceptor, the epsilon-amino group of lysine appeared to serve as a moderate acceptor of acridine moiety. The covalent modification of the lysine residues side chain in the hydrophobic core of prion protein aggregates could thus explain the discrepancy between the ability of the acridine drug quinacrine to reduce efficiently the incidence of prion protein in cell culture and its weak prion binding affinity.
New peptides-9-aminoacridine conjugates with an ethylene diamine linker-have been synthesized (both solution and solid phase methods were used) and their interactions with DNA have been studied. The affinity of H-Phe-Gln-Gly-Ile(2)-NHCH(2)CH(2)NH-Acr conjugate and of its extended analogue containing 6-aminohexanoic acid to DNA were lower than that of a standard H-Gly-NHCH(2)CH(2)NH-Acr conjugate. The results fit well into our concept of peptide conjugates with lowered binding activity to DNA, which could be capable of unlimited extravascular distribution. Moreover, new structures could be potentially useful as the mild tuners of DNA interaction with strong bis-acridine binders.
With the aid of labeling with stable isotopes ((15)N and (13)C) a complete set of chemical shifts and indirect spin-spin coupling constants was obtained for the zwitterionic form of L-alanyl-L-alanine in aqueous solution. Different sensitivities of the NMR parameters to the molecular geometry were discussed on the basis of comparison with ab initio (DFT) calculated values. An adiabatic two-dimensional vibrational wave function was constructed and used for determination of the main chain torsion angle dispersions and conformational averaging of the NMR shifts and coupling constants. The quantum description of the conformational dynamics based on the density functional theory and a polarizable continuum solvent model agrees reasonably with classical molecular dynamics simulations using explicit solvent. The results consistently evidence the presence of a single form in the aqueous solution with equilibrium main chain torsion angle values (psi = 147 degrees, varphi = -153 degrees), close to that one found previously in an X-ray study. Under normal temperature the torsion angles can vary by about 10 degrees around their equilibrium values, which leads, however, to minor corrections of the NMR parameters only. The main chain heavy atom chemical shifts and spin-spin coupling constants involving the alpha-carbon and hydrogen atoms appear to be most useful for the peptide structural predictions.
Dendrimers are branched structures and represent a fast growing field covering many areas of chemistry. Various types of dendrimers differing in composition and structure are mentioned, together with their practical use spanning from catalysis, transport vehicles to synthetic vaccines. The main stress is given to peptide dendrimers, namely, multiple antigenic peptides (MAPs). Their synthesis, physicochemical properties, biological activities, etc. have been described with many examples. MAPs can be used as diagnostics, mimetics, for complexation of different cations, as vaccines against parasites, bacteria, viruses, etc.
This work briefly describes available sensors for cAMP and cGMP. Many sensors are based on derivatization of naturally occurring products such as immunoglobulins, protein kinases, etc. Only a few published works deal with chemosensors, which are built up by "total" chemical synthesis. This field stays opened for combinatorial chemist. The best sensors are protein kinases genetically modified with mutants of green fluorescent protein, which allow screening of entire cell cultures.