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Biomedical subjects

G M Bonora

Publications and source records attributed to G M Bonora.

At least 19 recordsLinked to original sources
PubMed2001

Nuclease resistance and RNase H sensitivity of oligonucleotides bridged by oligomethylenediol and oligoethylene glycol linkers.

The properties of new chimeric oligodeoxynucleotides made of short sequences (tetramers, pentamers, octamers, and decamers) bridged by hexamethylenediol and hexaethylene glycol linkers have been investigated. These chimeric oligonucleotides showed an improved resistance toward snake venom 3'-phosphodiesterase, with an increased stability when a terminal 3'-3'-internucleotide phosphodiester bond is present. It also has been demonstrated that the hybrid complexes formed by bridged oligonucleotides and a complementary 20-mer RNA are able to elicit the activity of ribonuclease H (RNase H) from Escherichia coli. The substrate properties of chimeric oligonucleotides depend on the length of the oligonucleotide fragments bridged by linkers. Introduction of a nonnucleotide spacer into the native oligonucleotide only slightly hampers the extent of the RNA hydrolysis in the hybrid complexes, whereas a modification of the site of reaction is observed as a possible consequence of the steric disturbance due to the aliphatic linkers. Hence, these new chimeric oligonucleotides, namely, short oligonucleotide fragments bridged by nonnucleotide linkers, demonstrate a favorable combination of exonuclease resistance and high substrate activity toward RNase H. As a consequence, these chimeric oligonucleotides could be proposed as new, promising analogs to be used in the antisense strategy.

Ethylene Glycols↗
PubMed2000

Conformational restriction through C alpha i <--> C alpha i cyclization: Ac12c, the largest cycloaliphatic C alpha,alpha- disubstituted glycine known.

Two complete series of N-protected, monodispersed oligopeptide esters to the pentamer level from 1-aminocyclododecane-1-carboxylic acid (Ac(12)c), an alpha-amino acid conformationally constrained through C(alpha)(i) <--> C(alpha)(i) cyclization, and either L-Ala or Aib residues, along with the N-protected Ac(12)c homopeptide alkylamide series from monomer to trimer, have been synthesized by solution methods and fully characterized. The solution-preferred conformations of these peptides have been assessed by Fourier transform ir absorption and (1)H-nmr techniques. Moreover, the molecular structures of one derivative (Z-Ac(12)c-OH) and three peptides [the tripeptide ester Z-L-Ala-Ac(12)c-L-Ala-OMe, the tripeptide alkylamide Z-(Ac(12)c)(3)-NHiPr, and the tetrapeptide ester Z-(Aib)(2)-Ac(12)c-Aib-OtBu (Aib, alpha-aminoisobutyric acid)] have been determined in the crystal state by x-ray diffraction. The results obtained point to the conclusion that beta-bends and 3(10)-helices are preferentially adopted by peptides based on Ac(12)c, the largest cycloaliphatic C-disubstituted glycine known. A comparison with the structural tendencies extracted from published works on peptides from Aib, the prototype of C-disubstituted glycines, and the other extensively studied members of the class of 1-aminocycloalkane-1-carboxylic acids (Ac(n) c, with n = 3-9), is made and the implications for the use of the Ac(12)c residue in the Ac(n) c scan approach of conformationally restricted analogues of bioactive peptides are briefly discussed.

Alanine↗
PubMed2000

PAcM-AN: poly (N-acryloylmorpholine)-conjugated antisense oligonucleotides.

A new amphiphilic, high-molecular weight poly (N-acryloylmorpholine) (PAcM) polymer has been used to be linked to oligonucleotide chains through a liquid-phase stepwise synthesis. This new conjugate has been investigated for its melting property, nuclease stability and capacity to elicit RNase H activity. Its antisense activity against an HIV-1 target has been also evaluated.

Gene Expression Regulation↗
PubMed1998

Synthesis by High-Efficiency Liquid-Phase (HELP) Method of Oligonucleotides Conjugated with High-Molecular Weight Polyethylene Glycols (PEGs).

The chemical modification of synthetic oligonucleotides has recently been investigated to improve their pharmacological utilization. In addition to chemical alterations of the backbone and of the heterocyclic bases, their conjugation with amphiphylic moieties, such as the polyethylene glycol has been proposed. The large scale production of these molecules as demanded for commercial purposes is hampered by the heterogeneity of the solid-phase processes and by the low reactivity of high-molecular weight PEGs in solution. A new synthetic procedure based on the recently developed liquid-phase method (HELP), has been set up to overcome these limitations.

Journal Article↗
PubMed1995

The polypeptide 3(10)-helix as a template for molecular recognition studies. Structural characterization of a side-chain functionalized octapeptide.

A N alpha-blocked, Aib-rich octapeptide methylamide containing two N omega-benzoylated L-Lys residues at positions 3 and 6 was synthesized by solution methods and fully characterized. A solution and crystal-state conformational analysis, performed by using FT-IR, 1H NMR, CD, and X-ray diffraction techniques, showed that the peptide is folded into a regular, right-handed 3(10)-helix stabilized by seven consecutive N-H...O=C intramolecular H-bonds of the beta-turn III type. The two benzamidobutyl L-Lys side chains, located on the same side of the helix after one complete turn, generate a cleft the minimal width of which was found to be 3.47 A.

Amino Acid Sequence↗
PubMed1994

Defect peptide chemistry: perturbations in the structure of a homopentapeptide induced by a guest residue interrupting side-chain regularity.

The fully blocked pentapeptide Tfa-(Deg)2-L-Abu-(Deg)2-OtBu (Tfa: triflouroacetyl; Deg: C alpha, alpha-diethylglycine; Otbu: tert-butoxy) adopts in the crystal state a regular, right-handed 3(10)-helical structure stabilized by three N--H...O=C intramolecular 1 < 4 (or C10) H bonds, as determined by an x-ray diffraction analysis. However, a Fourier transform ir absorption and 1H-nmr study strongly supports the view that in deuterochloroform solution the four Deg residues at both termini of the peptide main chain are involved in successive, fully extended C5 forms. A comparison with the stable, fully developed, multiple C5 conformation of Tfa-(Deg)5-OtBu indicates that incorporation of an Abu guest residue, interrupting the side-chain uniformity of the host (Deg)5 homopeptide, while altering only marginally the conformation in a solvent of low polarity, is responsible for a dramatic perturbation of the crystal-state structure.

Amino Acid Sequence↗
PubMed1994

Onset of the fully extended conformation in (alpha Me)Leu derivatives and short peptides.

The X-ray diffraction crystal structures of the (alpha Me)Leu derivative mClAc-D-(alpha Me) Leu-OH and the terminally protected tripeptide Z-D-(alpha Me) Leu-(L-Ala)2-OMe show the onset of the fully extended (C5) conformation for the (alpha Me) Leu residue in both independent molecules in the asymmetric unit of the former compound and in two out of the four independent molecules in the asymmetric unit of the latter compound. In addition, conformational analysis in CDCl3 solution (using FT-infra-red absorption and 1H nuclear magnetic resonance) revealed the occurrence of a significant population of fully extended conformers throughout the entire sequence of the (alpha Me) Leu homochiral homopeptides pBrBz-[D-(alpha Me) Leu]n-OtBu (from monomer to tetramer). Taken together, these results represent a clear indication that this peptide secondary structure, uncommon for protein amino acids and other C alpha-methylated chiral residues, is not a rare observation in (alpha Me) Leu derivatives and short peptides.

Amino Acid Sequence↗
PubMed1993

Large scale, liquid phase synthesis of oligonucleotides by the phosphoramidite approach.

A new method for the liquid phase synthesis of oligonucleotides is described which makes use of polyethylene glycol (PEG) as soluble support and phosphoramidite derivatives as synthons. The new synthetic protocol was applied to a quite large scale production (about 100 mumoles) of such compounds up to the 20mer level. This solution method, called HELP High Efficiency Liquid Phase) Plus, appears effective in terms of speed and coupling yield and can be evaluated for the production of large amount of oligonucleotides.

Chromatography, High Pressure Liquid↗
PubMed1993

The beta-bend ribbon spiral. Synthesis and conformational analysis in solution and in the crystal state of depsipeptides containing alpha-hydroxyisobutyric acid.

The synthesis and conformational analysis in solution (by FTIR absorption and 1H NMR) and in the crystal state (by X-ray diffraction) of three Hib-containing depsipeptides have been performed. In the crystal state Z-Aib-Hib-Aib-OMe is folded into a type-III beta-bend, while the conformation adopted by Z-Aib-Hib)2-Aib-OMe is a beta-bend ribbon spiral, characterized by two type-III beta-bends with Aib(1)-Hib(2) and Aib(3)-Hib(4) as corner residues, respectively. Both independent molecules in the asymmetric unit of t-Boc-L-Ala-Hib-L-Ala-OMe crystals are folded into a type-II beta-bend. For the Aib-Hib depsipeptides the conformation adopted in the crystal state is also that largely prevailing in solution, whereas for t-Boc-L-Ala-Hib-L-Ala-OMe the beta-bend conformation is significantly less populated in solution. A comparison is also made with: (i) the published crystal-state conformations of fully protected -(Aib)3-, -(Aib)5-, and -L-Ala-Aib-L-Ala- sequences and the beta-bend ribbon spiral generated by (Aib-L-Pro)n oligomers, and (ii) with the herewith described solution preferred conformation of Z-L-Ala-Aib-L-Ala-OMe. The possible use of Hib as an isosteric replacement for Aib in the design of conformationally constrained depsipeptides is briefly discussed.

Amino Acid Sequence↗
PubMed1993

Synthesis and some properties of two salsalate derivatives.

The synthesis of esters of 2-hydroxy benzoic acid-2-carboxyphenyl ester (salsalate) with guaiacol for the treatment of inflammatory bronchopneumopathies is reported. The antiinflammatory, analgesic and antipyretic activities of these derivatives were evaluated, together with their antioxidant, mucolytic and broncho-bacteriostatic properties in comparison to acetylsalicylic acid.

Animals↗
PubMed1992

Monomer units for the beta-bend ribbon structure: MeAib peptides.

A conformational analysis in CDCl3 solution by using i.r. absorption and 1H nuclear magnetic resonance spectroscopy was performed on the fully blocked dipeptides Z-MeAib-Aib-NHMe, Z-MeAib-L-Ala-NHMe, Z-Aib-MeAib-NHMe, and Z-L-Ala-MeAib-NHMe, representing repeating units of the beta-bend ribbon spiral (an approximate 3(10)-helix, with an intramolecular H-bonding donor every two residues), where Z represents benzyloxycarbonyl, MeAib alpha-methylaminoisobutyric acid, and NHMe methylamino. The molecular and crystal structures of the first three compounds were also assessed by X-ray diffraction. While the -MeAib-Aib-, -MeAib-L-Ala-, and -Aib-MeAib- sequences give stable beta-bend structures, the preferred conformation of the -L-Ala-MeAib- sequence is open. These results indicate that the MeAib residue is a good beta-bend promoter, but less efficient than its unmethylated counterpart at position i + 2.

Dipeptides↗
PubMed1991

Preferred conformation of peptides from C alpha,alpha- symmetrically disubstituted glycines: aromatic residues.

The conformational preference of C(alpha,alpha-diphenylglycine (D-phi-g) and C(alpha,alpha)-dibenzylglycine (Dbz) residues was assessed in selected derivatives and small peptides by conformational energy computations, ir absorption, 1H-nmr, and x-ray diffraction. Conformational energy computations on the two monopeptides strongly support the view that these C(alpha,alpha)-symmetrically disubstituted glycines are conformationally restricted and that their minimum energy conformation falls in the fully extended (C5) region. The results of the theoretical analyses appear to be in agreement with the solution and crystal-state structural propensities of three derivatives and seven di- and tripeptides.

Amino Acid Sequence↗
PubMed1991

Peptides from chiral C alpha,alpha-disubstituted glycines. Synthesis and characterization, conformational energy computations and solution conformational analysis of C alpha-methyl, C alpha-isopropylglycine [(alpha Me)Val] derivatives and model peptides.

Conformational energy computations on Ac-L-(alpha Me)Val-NHMe indicate that turns and right-handed helical structures are particularly stable conformations for this chiral C alpha-methyl, C alpha-alkylglycyl residue. We have synthesized and characterized a variety of L-(alpha Me)Val derivatives and peptides (to the pentamer level). The results of the solution conformational analysis, performed using infrared absorption, 1H nuclear magnetic resonance, and circular dichroism, are in general agreement with those obtained from the theoretical investigation, in the sense that the L-(alpha Me)Val residue turns out to be a strong beta-turn and right-handed helix former. A comparison is also made with the conclusions extracted from published work on peptides rich in other C alpha-methyl, C alpha-alkylglycyl residues.

Circular Dichroism↗
PubMed1990

HELP (high efficiency liquid phase) new oligonucleotide synthesis on soluble polymeric support.

A simple, rapid and high-yielding method for the synthesis of oligonucleotides by the phosphotriesters approach is described. The use of polyethylene glycol (PEG) as soluble polymeric support preserves some convenient features of the solid-phase synthesis with new interesting advantages. Short oligonucleotides in hundred milligrams scale can be obtained from few grams of functionalized PEG.

Chromatography, High Pressure Liquid↗
PubMed1990

One pot solution synthesis of cyclic oligodeoxyribonucleotides.

Several cyclic oligodeoxynucleotides with different base composition and size have been prepared from 5',3'-unprotected linear precursors, using a bifunctional phosphorylating reagent. The final deprotected oligomers have been characterized by 1H- and 31P-NMR. The present procedure is particularly useful for millimolar scale syntheses.

Base Sequence↗
PubMed1989

Structural versatility of peptides containing C alpha, alpha-dialkylated glycines: conformational energy computations, i.r. absorption and 1H n.m.r. analysis of 1-aminocyclopropane-1-carboxylic acid homopeptides.

Conformational energy computations on the 1-aminocyclopropane-1-carboxylic acid mono-, di-, and tripeptide amides, Ac-(Ac3c)n-NHMe (n = 1-3), indicate that this C alpha, alpha-dialkylated, cyclic alpha-amino acid residue is conformally restricted and that type-I(I') beta-bends and distorted 3(10)-helices are particularly stable conformations for the di- and tripeptide amides, respectively. The results of the theoretical analysis are in agreement with those obtained in an i.r. absorption and 1H n.m.r. investigation in chloroform solution of Ac3c-rich tri- and tetrapeptide esters. A comparison is also made with the conclusions extracted from our previous work on peptides rich in Aib (alpha-aminoisobutyric acid), Ac5c (1-aminocyclopentane-1-carboxylic acid), and Ac6c (1-aminocyclohexane-1-carboxylic acid).

Alkylation↗
PubMed1989

Synthesis and biological activity of dansyl thymidines.

The synthesis of thymidines selectively dansylated in the 3'- and 5'-positions is reported. The biological investigation showed that these fluorescent nucleosides behave as competitive inhibitors of thymidine kinase (TK) from herpes simplex virus (HSV) and are endowed with a certain degree of antiviral activity against HSV-2 and HSV-1.

Antiviral Agents↗