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Biomedical subjects

V Pavone

Publications and source records attributed to V Pavone.

At least 91 records · Page 5Linked to original sources
PubMed1994

Congenital muscular dystrophy with syringomyelia.

We report a 7-year-old boy with congenital muscular dystrophy with severe spinal deformation and low thoracic syringomyelia, which may represent a novel form of the disease with muscle involvement and spinal cord anomaly. We suggest that patients with congenital muscular dystrophy who manifest skeletal anomalies undergo spinal magnetic resonance imaging to detect potential spinal cord abnormalities, in addition to cranial magnetic resonance imaging to detect potential cerebral malformations.

Biopsy↗
PubMed1994

MEN 10,627, a novel polycyclic peptide antagonist of tachykinin NK2 receptors.

We describe the in vitro and in vivo pharmacological properties of MEN 10,627 or cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2 beta-5 beta), the first example of a polycyclic peptide tachykinin NK2 receptor antagonist. MEN 10,627 is endowed with high affinity for NK2 receptor expressed in various species with pKB values ranging between 10.1 (hamster trachea) and 8.1 (rabbit pulmonary artery). The antagonism is of competitive type in both functional and radioligand binding assays. A 100- to 10,000-fold selectivity was found vs. NK1 or NK3 receptors expressed in various species. As an NK2 receptor antagonist, MEN 10,627 is 10- to 100-fold more potent than the monocyclic peptide antagonist L 659,877 or cyclo(Met-Gln-Trp-Phe-Gly-Leu). At the hamster NK2 receptor, MEN 10,627 is about 30-fold more potent than the nonpeptide NK2 receptor antagonist SR 48,968 [(S)-N-methyl-N[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl]benzamide], whereas the converse is true for the rabbit NK2 receptor. Furthermore, MEN 10,627 is, up to micromolar concentrations, devoid of antagonist properties toward a wide range of transmitters of both peptide and nonpeptide nature. In urethane-anesthetized rats in vivo, MEN 10,627 (10-100 nmol/kg i.v.) produced long-lasting inhibition of contraction of the urinary bladder and duodenum produced by i.v. administration of the NK2 receptor agonist [beta Ala8]NKA(4-10), without affecting the responses produced by i.v. administration of the NK1 receptor agonist [Sar9]SP sulfone or acetylcholine. In anesthetized rats, both MEN 10,627 and SR 48,968 blocked urinary bladder contraction induced by the NK2 receptor agonist after intravenous, intranasal or intraduodenal administration. Equieffective doses of MEN 10,627 producing about 50% inhibition of the response to [beta Ala8]NKA(4-10) in the rat urinary bladder in vivo, were 0.01, 0.03 and 3 mumol/kg after intravenous, intranasal and intraduodenal administration, respectively. The corresponding doses of SR 48,968 were 0.03, 0.1 and 1 mumol/kg, after intravenous, intranasal and intraduodenal administration, respectively. In conclusion, MEN 10,627 is a potent and selective NK2 receptor antagonist, endowed with high potency and long duration of action in vivo, which is not restricted to parenteral administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1993

beta-Alanine containing peptides: gamma-turns in cyclotetrapeptides.

In the present paper we describe the synthesis, purification, single-crystal x-ray analysis, solution conformational characterization, and conformational energy calculations of the cyclic tetrapeptide cyclo-(beta-Ala-L-Pro-beta-Ala-L-Val). The peptide was synthesized by classical solution methods and the cyclization of the free tetrapeptide was accomplished in good yields in diluted methylene chloride solution using N,N-dicyclohexyl-carbodiimide. The compound crystallizes in the monoclinic space group P2(1) from ethanol with two independent molecules in the unit cell. All peptide bonds are trans. The nmr molecular conformation in the acetonitrile solution as well as that derived from the molecular dynamic simulation in vacuo is quite different from those observed in the solid state and is very similar to that previously observed for the parent compound cyclo- (beta-Ala-L-Pro-beta-Ala-L-Pro).

Amino Acid Sequence↗
PubMed1993

Noncoded residues as building blocks in the design of specific secondary structures: symmetrically disubstituted glycines and beta-alanine.

Structural changes can be induced in a peptide by selective substitution of coded alpha-amino acid residues by noncoded alpha-amino acid residues and the consequent production of analogues with modified structure and conformational preferences. In this review article we summarize the solid state structural results and the conformational preferences of two classes of "building blocks": (a) the linear and cyclic symmetrically alpha, alpha-disubstituted glycines in which either two identical n-alkyl groups replace the hydrogen atoms of the glycine residue or a cyclic aliphatic side-chain system is formed by linking the two alpha-carbon side chains, respectively; and (b) the beta-alanine residue. Examples, whenever possible, of the use of these residues for the elucidation of the bioactive conformation in the appropriate biological systems will be given.

Amino Acid Sequence↗
PubMed1993

Conformational versatility of the N alpha-acylated tripeptide amide tail of oxytocin. Synthesis and crystallographic characterization of three C2 alpha-backbone modified, conformationally restricted analogues.

The synthesis, physical and analytical characterization, and crystal-state structural analysis by X-ray diffraction of three analogues of the N alpha-acylated tripeptide amide tail of oxytocin, each containing a cyclic C alpha, alpha-disubstituted glycine at position 2, have been performed. The peptides are Boc-L-Pro-Ac3c-Gly-NH2, Z-L-Pro-Ac5c-Gly-NH2 and Z-L-Pro-Ac6c-Gly-NH2. While the former is folded in a type-II beta-turn conformation at the -L-Pro-Ac3c- sequence, the two latter tripeptides form two consecutive (type-II, type-I') beta-turns. The Ac5c- and Ac6c-tripeptides are the first examples of such a highly folded structural combination in a position-2 analogue of the N alpha-acylated -L-Pro-L-Leu-Gly-NH2 sequence.

Acylation↗
PubMed1993

Non coded C alpha, alpha-disubstituted amino acids. X-ray diffraction analysis of a dipeptide containing (S)-alpha-methylserine.

The crystal and molecular structure of the fully protected dipeptide Boc-Val-(S)-alpha-MeSer-OMe has been determined by X-ray diffraction techniques. Crystals grown from ethyl acetate/n-pentane mixtures are tetragonal, space group I4(1), with cell parameters at 295 K of a = 15.307(2), c = 18.937(10)A, V = 4437.1A3, M.W. = 332.40, Z = 8, Dm = 0.99 g/cm3 and Dx = 0.995 g/cm3. The structure was solved by application of direct methods and refined to an R value of 0.028 for 1773 reflections with I > or = 3 sigma (I) collected on a CAD-4 diffractometer. Both chiral centers have the (S) configuration. The dipeptide assumes in the solid state an S shape. The urethane moiety is in the cis conformation, while the amide bond is in the common trans conformation. The conformational angles phi 1, psi 1 of the Val and phi 2, and psi 2 of the (S)-alpha MeSer fall in the F region of the phi-psi map. The isopropyl side chain of the Val residue has the (t, g-) conformation, while the Ser side chain has a g+ conformation. The hydrogen bond donor groups are all involved in intermolecular H-bond interactions. Along the quaternary axis the dipeptide molecules are linked to each other with the formation of infinite rows.

Crystallization↗
PubMed1992

Conformation for a beta-cyclodextrin monosubstituted with a cyclic dipeptide.

The structural characterization of a beta-cyclodextrin monosubstituted with the peptide cyclo(L-His-L-Leu) is reported. This work provides an x-ray example of a covalently bound group that folds in such a way that the terminal apolar side chain is retained in the hydrophobic interior of the cone-shaped cyclodextrin cavity. 6-Deoxy-6-cyclo(L-histidyl-L-leucyl)-beta-cyclodextrin crystallizes in the space group P1 with cell dimensions a = 14.728(8) A, b = 15.084(7) A, c = 18.182(10) A, alpha = 94.36(6) degrees, beta = 95.81(5) degrees, gamma = 116.08(9) degrees; overall isotropic agreement R = 10.6% for 5703 observed reflections (Fo greater than 3 sigma). The molecular structure consists of two independent molecules with the formula C54H86N4O36.7.25H2O. Each molecule assumes a "sleeping swan"-like overall shape with the hydrophobic leucine side chain inserted inside the cavity of the macrocycle. The two independent units give rise to a head-to-tail dimer linked by hydrogen bonds occurring between primary and secondary hydroxyl groups of the two monomers. The packing of the dimers produces cavities containing water molecules. There are infinite hydrophilic channels running in the crystal, which is similar to what is found in the structures of cyclic peptides.

Carbohydrate Conformation↗
PubMed1992

Beta-alanine containing peptides: a novel molecular tool for the design of gamma-turns.

In the present paper we describe the synthesis, purification, single crystal x-ray analysis, and solution conformational characterization of the cyclic tetrapeptide cyclo-(L-Pro-beta-Ala-L-Pro-beta-Ala). This peptide was synthesized by classical solution methods and the cyclization of the free tetrapeptide was accomplished in good yields in diluted methylene chloride solution using N,N-dicyclohexyl-carbodiimide (DCCI). The compound crystallizes in the orthorombic space group P2(1)2(1)2(1) from ethyl acetate. All peptide bonds are trans. The molecular conformation is stabilized by two intramolecular hydrogen bonds between the CO and NH groups of the two beta-alanine residues. These hydrogen bonds take place in a C7 structure in which both proline residues occupy the 2 position of an inverse gamma-turn. The two beta-alanine residues have a typical folded conformation (around the C alpha-C beta bond) observed in other cyclic peptides containing this residue. A detailed 1H-nmr analysis in CD3CN solution has been carried out. The molecule assumes a twofold symmetry in solution with a molecular conformation consistent with that observed in the solid state.

Amino Acid Sequence↗
PubMed1992

Characterization at atomic resolution of peptide helical structures.

A survey of literature for the various types of helices experimentally observed in high-resolution single crystal x-ray diffraction analyses of peptides has allowed to determine accurate conformational and helical parameters for the various secondary structures such as the alpha-helix, the 3(10)-helix, the fully extended conformation (2(5)-helix) and the beta-bend ribbon spiral. For each of these structures the characteristic phi, psi conformational parameters, n, the number of residues per turn, h, the height per residues and p, the pitch of the helix are described.

Models, Molecular↗
PubMed1992

Conformation of diastereomeric peptide sequences: structural analysis of Z-D-Val-Ac6c-Gly-L-Phe-OMe.

We have recently undertaken a systematic structural analysis of fully protected tetrapeptides containing at the N- and C-terminus either homo- or heterochiral amino acids, spaced by an achiral dipeptide segment. The interest for this class of peptides derives from the observation that, on reverse-phase (HPLC), the homo- and heterochiral sequences have a markedly different retention times. The diastereomeric sequences, namely Z-(L/D)-Val-X-Y-L-Phe-OMe (X = Sar, Gly, Ac3c, Aib, Ac5c, Ac6c, Deg, Dpg, Dbu, Dip, Dph; Y = Sar, Gly, Ac3c, Aib, Ac5c, Ac6c) show different overall hydrophobicity attributed to a different three-dimensional structure that also depends on the X-Y segment. Therefore, following preliminary studies in solution, we report here the detailed x-ray analysis of the tetrapeptide Z-D-Val-Ac6c-Gly-L-Phe-OMe in order to understand the structural features governing the overall hydrophobicity of linear fully protected tetrapeptides.

Amino Acid Sequence↗
PubMed1992

Molecular dynamics simulation in vacuo and in solution of [Aib5,6-D-Ala8] cyclolinopeptide A: a conformational and comparative study.

The conformation of a Cyclolinopeptide A analogue, c-(Pro-Pro-Phe-Phe-Aib-Aib-Ile-D-Ala-Val), has been investigated by means of molecular dynamics simulations, in various molecular environments. The molecular dynamics results are compared with that obtained for Cyclolinopeptide A and a detailed analysis of the different behaviour for the two compounds is reported. A complete analysis of hydrogen bonds is presented.

Amino Acid Sequence↗
PubMed1992

Mitoxantrone and continuous infusion of cytosine arabinoside in refractory and relapsed acute lymphoblastic leukemia.

Twenty adult patients with relapsed or refractory acute lymphoblastic leukemias (ALL) received a regimen employing two courses of mitoxantrone 12 mg/m2 by rapid intravenous infusion on days 1, 2 and 3 and cytosine arabinoside (ARA-C) 200 mg/m2/day by continuous infusion on days 1-7. Complete remission (CR) was achieved in 10 of 20 (50%) patients (3 refractory and 7 relapsed). Median duration of CR was 5 months (range 2-9). The treatment was associated with minimal extrahematologic toxicity, with no cardiac toxicity. Our results are nearly in line with therapeutic responses obtained with regimens employing megadose therapy (HD ARA-C). Because of acceptable toxicity, mitoxantrone plus continuous infusion of a standard dose of ARA-C could be considered for relapsed of refractory ALL patients eligible for an intensive therapeutic approach (bone marrow transplantation) after a second CR.

Adolescent↗
PubMed1991

beta-Alanyl-beta-alanine in cyclic beta-turned peptides.

In the present paper we describe the synthesis, purification, and single crystal x-ray analysis of the cyclic pentapeptide cyclo-(L-Pro-L-Pro-L-Phe-beta-Ala-beta-Ala). The peptide was synthesized by classical solution methods and the cyclization of the free pentapeptide was accomplished in good yields in diluted methylene-chloride solution using N,N-dicyclohexylcarbodiimide. The compound crystallizes in the monoclinic space group P21 from hot water with five solvent molecules. The Pro1-Pro2 peptide bond is cis and the molecular conformation is stabilized by an intramolecular hydrogen bond between the CO group of the beta-Ala5 and the NH of the Phe3 residue. The Pro1-Pro2 segment occupies the relative positions 2 and 3 of a type VIa beta-turn, while the L-phenylalanyl-beta-alanyl-beta-alanine segment is incorporated in a C13-like ring structure. The crystal packing is characterized by a network of 11 intermolecular hydrogen bonds involving all the remaining CO, NH, and the water molecules.

Crystallography↗
PubMed1991

[Lymph nodes of the neck. Diagnosis using magnetic resonance with gradient-echo technique].

As for the pathologic conditions of neck lymph nodes, the clinician needs to know if the involved node is reactive, phlogistic, or neoplastic in nature. If accurate tumor staging is required, imaging techniques play a fundamental role. Our study was aimed at assessing the actual role of MR imaging in the evaluation of neck lymph node involvement. The study was performed using an MR Max Plus by General Electrics operating with an 0.5 T superconductive magnet. We employed gradient-echo (GE) pulse sequences with TR 500, TE 15 ms and 90 degrees flip angle for T1-weighted images, and with TR 500, TE 30 ms and 25-30 degrees flip angles for T2-weighted images; for Pd-T2-weighted images, TR was 520, TE 30 ms, and flip angles were 40-45 degrees. The results were correlated with histopathologic findings obtained at biopsy. The advantages of GE sequences were: 1) whole neck imaging--thus saving time, and reducing radiation dose and contrast media; 2) optimal anatomical and topographic evaluation of the lesion; 3) imaging of the longitudinal diameter of the node; 4) higher sensitivity for lymph node tissue modifications; 5) imaging of necrosis, hemorrhage, and/or fibrosis. GE sequences were especially useful for accurate tumor staging, in the follow-up, and to verify response to therapy. However, even though MR imaging has proven to have high sensitivity, its specificity was similar to that of contrast-enhanced CT. Further studies with the use of paramagnetic contrast media are needed to solve these problems.

Diagnosis, Differential↗
PubMed1990

The longest, regular polypeptide 3(10) helix at atomic resolution.

A synthetic, terminally blocked homodecapeptide from the C alpha, alpha-dimethylated glycyl residue alpha-aminoisobutyric acid has been analyzed by single-crystal X-ray diffraction and the structure refined to R = 0.073. The compound crystallizes as a perfect 3(10) helix, stabilized by eight consecutive intramolecular N-H . . . O = C hydrogen bonds. This is the first observation at atomic resolution of a regular polypeptide 3(10) helix as long as three complete turns.

Aminoisobutyric Acids↗
PubMed1990

Stereochemical behavior of acyclic peptide-cation complexes.

The role of the beta-turns in the peptide interaction with several cations was investigated. In this work we report the solution studies of four linear peptides: Z-Aib-Aib-Aib-L-Val-OMe, Boc-D-aIle-L-Ile-D-aIle-L-Ile-OMe, Boc-L-Leu-L-Leu-L-Leu-L-Leu-OMe, and Boc-L-Phe-D-Phe-L-Phe-D-Phe-OMe. CD and 1H-nmr spectra reveal the presence of multiple ion-bonding equilibria. The stoichiometry and binding constant of the four peptides in the presence of Ca2+ ions in acetonitrile solution has been determined. Variable-temperature nmr spectra in the absence and in the presence of a large excess of cation have shown that the complexation process is not critically dependent on the conformation of the free peptide.

Amino Acid Sequence↗
PubMed1990

Continuous infusion chemotherapy with epirubicin and vincristine in relapsed and refractory acute leukemia.

Twenty-three patients admitted for treatment of refractory or relapsed acute leukemias (12 acute nonlymphocytic leukemias, 4 acute lymphocytic leukemias, 1 acute undifferentiated leukemia, 6 chronic myeloid leukemias in blast crisis) received a regimen employing a 4-day continuous intravenous infusion of epirubicin followed by a 4-day continuous infusion of vincristine. The remission rate (complete and partial) was 52%. This treatment was associated with minimal extrahematologic toxicity, particularly cardiac and gastrointestinal toxicity. This method of administration should be considered a reasonable therapeutic approach to pretreated acute leukemia patients, particularly in elderly patients wishing to avoid chemotherapy-related side effects.

Acute Disease↗