Browsing by Subject "peptidomimetics"
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Item C10 semi-peptoid beta-turn peptidomimetics: syntheses, characterization and biological studies(2009-06-02) Nnanabu, ErnestOver the years, the Burgess group has been focusing on the preparation and testing of small molecules that mimic protein secondary structures for protein-protein interactions. The most successful compounds made are C10 peptide macrocycles that effectively mimic ??-turns and have given promising results from biological testing. These peptide macrocycles have also been dimerized to give even more effective ligands for protein-protein interaction. The successes of the peptide macrocycles have enabled us to look into increasing the chemical diversity of our libraries. This we believe will not only improve our ability to obtain high affinity ligands for the receptors of interest, but will also allow us to investigate other receptors. To achieve this, peptoids were incorporated into the C10 system to replace the peptides in the i+1 and i+2 positions. With the help of Microwave irradiation, semi-peptoid macrocycles were synthesized with a total reaction time of less than 2 h. These compounds were characterized and found to mimic ??-turn, and show promising biological activity towards the Insulin-like growth factor 1 receptor (IGF-IR).Item Contributions to peptidomimetic design: predictive computational studies and syntheses of linker molecules(Texas A&M University, 2007-04-25) Lam, Sang Q.In an effort to partially mimic the complex interaction between nerve growth factor (NGF) and its membrane-bound tyrosine kinase A receptor (TrkA), several small organic molecules with functionalities similar to the side-chains of the amino acid residues of NGF critical to binding were devised. These molecules were studied computationally using the program Affinity. Each molecule was individually docked onto one of the binding sites on TrkA as determined by mutagenesis studies and the x-ray crystal structure obtained from the Protein Data Bank. One of the strategies to enhance binding of active peptidomimetics to their target proteins is to link them together to form either homodimers or heterodimers. However, these dimers have low solubility in water and mimic only residues that are close together on the protein. Triethylene oxide- and hexaethylene oxide-based linker molecules were designed to circumvent these limitations. The increased polarity will improve the watersolubility and the added lengths, which can be controlled and varied by simple chemical manipulations, will allow for mimicking critical residues that are farther apart on the protein.Item Expanding beta-turn analogs for mimicking protein-protein hot spots(2009-06-02) Reyes, Samuel Onofre J.Solid-phase syntheses of two 14-membered ring peptidomimetics were done to determine whether or not a beta-turn structure can facilitate macrocyclization. NMR methods, together with CD and QMD calculations, do not fully support this assumption. However, cyclizations of more ordered structures like those of compounds 2 were more efficient than those for highly strained ring systems like 1. A small library of 18-membered ring peptidomimetics that accommodate an extra amino acid residue was synthesized on resin. Their syntheses were not complicated by head-to-tail dimer impurity, unlike those for previously synthesized 14-membered systems. These larger macrocycles exhibit beta-turn structures as verified by NMR, CD and QMD techniques. Moreover, two compounds in this series (3a and 3g) were shown to have agonistic properties for TrkC in cell survival assays. Dimerization of monovalent mimics was achieved first by modifying the organic template so that monovalent mimics with requisite functional groups can be synthesized. Second, the monovalent units were dimerized using sequential nucleophilic substitutions on fluorescently labeled dichlorotriazine. Our rationale to make bivalent compounds out of monovalent ones was justified when compound 4 was shown to bind TrkA with a 20 nM affinity. Reactions of amino acids with NH4SCN under acylating conditions produced 2-thiohydantoins in which the nitrogen of the amino acid (N1) was acylated. This was proven by 2-D NMR which showed no cross-peak between the NH signal observed and the C??-H of the amino acid. When the compound was deacylated, a new NH signal appeared and the corresponding cross-peak with the C??-H was observed. Solution-phase syntheses of non-peptidic mimics were achieved by doing a double substitution on a dihalogenated nitrobenzene scaffold. Sonogashira and SNAr reactions were done to install the required side-chains to give the desired compounds. These non-peptidic compounds can be easily adapted to our DTAF-Inp dimerization protocol since the nitro groups can be easily reduced. Attempts to make a spirotetracyclic peptidomimetic with three side chain mimics were done by synthesizing the spirocyclic diketopiperazine precursor. The synthesis of the DKP was achieved by making the cyclic quaternary amino acid that was coupled to another amino acid via the HOAt-EDC method. This protocol gave dipeptides in high yields. These dipeptides were deprotected and cyclized to the DKP under mildly acidic conditions in toluene.Item Peptidomimetics to mimic protein-protein interactions(Texas A&M University, 2005-08-29) Xia, ZebinQuenched Molecular Dynamics (QMD) used to explore molecular conformations was developed to operate in Insight II platform for two simulation engines: CHARMm and Discover. Two scripts and procedures were written for molecular minimization, dynamics, minimization of each of several hundred conformers, and cut off. Experience with Insight II/Discover versus Quanta/CHARMm, and between Insight II/CHARMm versus Quanta/CHARMm has taught that the forcefield is the key factor in QMD studies. Protein A has been used for the purification of commercial antibodies, but it is expensive. Seven peptidomimetics of protein A were designed based on the hot-spots located at the helix-loop-helix region of protein A, and synthesized via solid phase using the Fmoc approach. These peptidomimetics were characterized by MS and NMR. The conformations of four peptidomimetics were studied by NMR and CD in water/hexafluoroisopropanol (pH 4). The CD and NMR data show that addition of hexafluoroisopropanol stabilizes their a-helical conformations. The structures of these peptidomimetics in solution were generated with Quanta/CHARMm using NMR data as limits for the QMD technique. Protein G has also been used to purify antibodies, but it is expensive too. A number of protein G mimics were designed as trivalent molecules. An efficient preparation of trivalent molecules having a useful primary amine arm has been developed through solid phase synthesis. The cheap, commercially available poly(propylene imine) dendrimers were used as scaffolds which allow multimerization of functionalized compounds. A small library of trivalent compounds were synthesized using this approach. A portion of compounds in this library were tested by Amersham Biosciences. The seven amino acid modified DAB-Am-4 exhibits strong binding to the IgG/Fab, and is a potential ligand for IgG purification. The interactions between neurotrophins (ie NGF and NT-3) and their receptors are typical drug targets. Fourteen second-generation peptidomimetics showing NGF-like or NT3-like activities in a preliminary bioassay, were resynthesized and tested again. Preliminary and retested data were compared. To access a direct binding assay, five fluorescently labeled peptidomimetics 41a-e were synthesized for a fluorescence activated cell sorting (FACScan) assay. Six monomeric precursors 42 and 43 were prepared on large scales for the library of bivalent turn analogsItem Triazole based peptidomimetics for mimicking protein-protein hot spots(2009-05-15) Angell, Yu LiCopper-mediated alkyne-azide cycloadditions yield 1,4-disubstituted triazoles with high chemoselectivity that can be used in many ways. For instance, when alkyne or azido peptide units combine via this pathway the reaction is relatively insensitive to the amino acid side-chains. This serves as an excellent way to produce peptidomimetics, particularly because there is some stereoelectronic similarity between 1,2,3-triazoles and amide bonds. Linear peptidomimetic substrates 60 were used to form the cyclic derivatives 61 via copper catalyzed azide alkyne cycloadditions. This reaction is fast, simple to perform and compatible with many solvents and functional groups. A library of eight cyclic peptidomimetics was prepared in solution and the low yield was mostly due to formation of dimers. Computational, NMR, and CD analyses of compounds 61a-c indicate that their most favorable conformational states include type I and type II ?-turn conformations. Monovalent triazole mimics were prepared via cycloaddition reactions in solution. These triazole compounds contain two amino acid chain functionalities at 1- and 4- positions. One is derived from a natural amino acid and the other is a functional group that resembles the side chains of an amino acid. The 1,3-dipolar cycloaddition reactions allow quick and efficient generation of the desired peptidomimetics in good yields. Two monovalent mimics were coupled to the linker scaffold sequentially in solution by simply manipulating the solvent systems. This method allows us to prepare large libraries of bivalent compounds quickly and efficiently. The two monomers were combined with each other cleanly, to achieve one-compound-per-well in sufficient purity for biological testing. Oxidative coupling to give 5,5?-bistriazoles is discussed. The bistriazole products predominate in the copper accelerated ?click reaction? of alkynes and azides when carbonate bases are used as additives (ca 1 ? 2 M). The reaction seems to be more efficient for propargylic ethers and less hindered substrates. Use of optically active azides could afford separable atropisomeric products, providing a convenient access into optically pure derivatives.