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M Marastoni

Publications and source records attributed to M Marastoni.

At least 55 records · Page 3Linked to original sources
PubMed1991

Synthesis and structure-activity relationships of deltorphin analogues.

In order to study the structure-activity relationships of natural opioid deltorphins (H-Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2 and H-Tyr-D-Ala-Phe-Asp [or Glu]-Val-Val-Gly-NH2), 15 analogues were synthesized by the solution method. Their activities were determined in binding studies based on displacement of mu- and delta-receptor selective radiolabels from rat brain membranes and in two bioassays, using guinea pig ileum and mouse vas deferens. The obtained data indicate that the high delta-selectivity of deltorphins can be due to the constitution/conformation of the C-terminal part and, at least in part, to preselection by charge.

Amino Acid Sequence↗
PubMed1991

On the degradation of the deltorphin peptides by plasma and brain homogenate.

The peptidase-resistance of deltorphins (DEL-A, H-Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2) and (DEL-C, H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2), highly selective and potent agonists of the delta opioid receptor, were investigated in vitro. DEL-C was fully resistant to degradation by rat plasma and strongly resistant to degradation by rat brain homogenates. DEL-A was cleaved with a half-life of 131.6 min upon incubation with plasma, and 57.4 min with rat brain homogenates. N-terminal truncated sequences of DEL-A and -C with free carboxyl groups, were also analyzed for receptor binding activity using [3H] DADLE for delta sites and [3H] DAGO for mu sites. The high enzymatic stability associated with deltorphins and their degradation products may make them prime candidates to characterize the role of delta-receptors in vivo.

Amino Acid Sequence↗
PubMed1990

New features of the delta opioid receptor: conformational properties of deltorphin I analogues.

Deltorphin I is an opioid peptide of sequence H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2, recently isolated from the skin of Phyllomedusa bicolor. Its enormous selectivity towards the delta opioid receptor and the similarity of the conformation of the N-terminal part of the sequence with that of dermorphin (H-Tyr-D-Ala-he-Gly-Tyr-Pro-Ser-NH2), a mu selective peptide, prompted the synthesis, biological evaluation and comparative conformational study of four analogs. A 1H-NMR study showed that the conformational preferences of the N-terminal sequences of all peptides are similar. The different selectivities towards opioid receptors have been interpreted in terms of charge effects in the interaction with the membrane and at the receptor site and of hydrophobicity of the C-terminal part, when structured in a folded conformation.

Amino Acid Sequence↗
PubMed1990

Chemotactic response of human monocytes to pentapeptide analog derived from immunodeficiency virus protein gp 120.

The octapeptide sequence of peptide T is contained within the envelope of HIV and seems to mediate the viral binding to CD4 expressing cells, including monocytes. The biological activity of the alpha-aminobutyric acid pentapeptide derived from the C-terminal sequence of peptide T, in which the polar side chain of threonine in position 4 is substituted by a hydrophilic group, is measured by the monocyte chemotaxis assay. The chemotactic activity of human monocytes is assessed by determining the concentration at which the pentapeptide analog is maximally active and the effectiveness at that concentration, in comparison with peptide T and two shorter homologs, the pentapeptide and tetrapeptide. These experiments suggest that the synthetic analog is a potent chemotactic factor active at picomolar concentrations and that it competes with peptide T for the monocyte binding site.

Chemotaxis, Leukocyte↗
PubMed1990

Synthesis, metabolic stability and chemotactic activity of peptide T and its analogues.

Acquired immunodeficiency syndrome (AIDS) is initiated by the attachment of the human immunodeficiency virus (HIV) to a surface glycoprotein CD4 present on T4 helper/inducer lymphocytes, monocytes/macrophages and other cells. A simple octapeptide (H-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-OH, peptide T) seems to inhibit HIV infectivity and to activate human monocyte chemotaxis. In order to study in vitro metabolic stability and structure-activity relationships, peptide T and a number of analogues were prepared and tested on human monocytes by chemotactic assay. Peptide T and the shorter fragments T(3-8)-OH and T(4-8)-OH displayed potent bioactivity (maximal chemotactic activity in the range 10(-11)-10(-10) M). The C-terminal heptapeptide showed a reduction of potency, while further truncations at N-terminus of T(4-8)-OH abolished the biological action. In the octapeptide series, whereas the alpha-amino butyric acid (Abu) substitution for Thr4 was well tolerated, the same "slight" structural change at Thr5 or Thr8 was very detrimental. Finally, [D-Asn6]T(1-8)-OH analogue has low chemotactic activity. All these results indicate that i) the C-terminal pentapeptide is the minimum sequence required for bioactivity, ii) residues 5 to 8 appear to play a crucial biological role, iii) peptide T chemotaxis is mediated, at least in part, through the polar properties of Thr side chains at the critical positions 5 and 8, while the Thr4 does not interfere with biological characteristics of peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1989

Conformational properties of deltorphin: new features of the delta-opioid receptor.

Deltorphin is an opioid peptide with the sequence H-Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2, recently isolated from the skin of Phyllomedusa sauvagei. Its enormous selectivity towards the delta-opioid receptor and the similarity of the N-terminal part of the sequence with that of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), a mu selective peptide isolated from the same natural source, prompted a comparative conformational study. A 1H-NMR study in two different solvent systems showed that the conformational preferences of the N-terminal sequences of the two peptides are similar. The different selectivities towards opioid receptors have been interpreted in terms of charge effects. Besides a general trend consistent with the role of the membrane in the preselection of the peptides, the present study demonstrates the crucial role played by charged residues in the interaction inside the receptors.

Amino Acid Sequence↗
PubMed1989

Conformational analysis of peptide T and of its C-pentapeptide fragment.

The synthetic peptide of sequence H-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-OH, termed peptide T, a competitor of the Human Immunodeficiency Virus in the binding to human T cells, and its C-terminal pentapeptide fragment, were studied by 1H-nmr in DMSO solution to determine conformational preferences. The observation of nuclear Overhauser enhancements (NOEs) for both peptides, and unusual finding for small linear peptides, allowed complete sequence-specific resonance assignments. Long-range NOEs, ring-current shifts, and the very small temperature coefficient of the Thr8 NH chemical shift suggest, for the zwitterionic form of peptide T, the presence in solution of a beta-turn involving Thr5, Asn6, Tyr7 and Thr8. This conformational feature is consistent with previous structure-activity relationship studies indicating the invariance of the same residues in several potent pentapeptide analogues. The studied pentapeptide fragment, although less structured, shows some tendency to fold even in a polar solvent such as DMSO. Preliminary chemotaxis data on some pentapeptide analogues are consistent with our structural model.

HIV↗
PubMed1989

Opioid peptides. Synthesis and binding properties of dermorphin related heptapeptides.

C-Terminal amino acid residues of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) were replaced by N alpha-methyl- or D-amino acids in order to examine the effect on opioid activity. In binding studies based on displacement of mu, delta, and kappa opioid receptor selective radiolabels from guinea pig brain membranes, the 13 new analogues showed, like dermorphin, a negligible affinity for the kappa binding site. The introduction of N alpha-methyl- or D-amino acid residues at position 5, 6, or 7 of dermorphin, when matched with C-terminal amide function modifications, generally produced analogues with reversed mu/delta specificity.

Amino Acid Sequence↗
PubMed1989

Synthesis and activity of dermorphin-growth hormone releasing factor hybrid peptides.

Dermorphin- growth hormone releasing factor (GRF) hybrid peptides (Y-Tyr-D-Ala-Xaa-Gly-Tyr-Pro-Ser-NH2) were synthesized and tested for opioid activity and their ability to stimulate growth hormone (GH) secretion. The substitution of Phe3 for Asp and Glu in dermorphin or its N-terminal acetylation produced peptides with no affinity for opioid receptors but significant, even if low, GRF-like activity.

Animals↗
PubMed1989

Opioid peptides. Partially modified retro-inverso dermorphin analogues. XIII.

We studied the effect of partial retro-inverso modification of a selected peptide bond of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) related peptides. The drastic loss of mu-receptor affinity following introduction of retro-inverso peptide bond between Phe1-D-Ala2 in the new peptide analogues, emphasized the importance of this backbone in the dermorphin peptides.

Amino Acid Sequence↗
PubMed1989

Structure-activity relationships of peptide T-related pentapeptides.

Fifteen pentapeptide analogs of C-terminal fragment of peptide T, H-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-OH, were prepared and tested for human monocyte chemotaxis. Structure-activity studies suggest that the potent chemotactic activity of H-Thr-Thr-Asn-Tyr-Thr-OH is mediated through the polar properties of the C-terminal carboxyl group and Thr side chains at the critical positions 5 and 8, while the hydroxyl group of N-terminal Thr and its free amino function are not essential requirements for CD4 receptor interactions.

CD4 Antigens↗
PubMed1988

A 500 MHz study of peptide T in a DMSO solution.

Peptide T, an octapeptide of sequence ASTTTNYT that binds to human T cells, was studied as a zwitterion in DMSOd6 solution by means of proton NMR spectroscopy at 500 MHz. The unusual dispersion of the resonances of residues of the same type (T) makes it possible to assign all resonances to specific residues by means of several 2D techniques. The non-random nature of the conformation is substantiated by the observation of sequential nuclear Overhauser enhancements (NOEs). The low value of the temperature coefficient of the chemical shift of the NH of T8 and a diagnostic NOE between the NHs of T7 and T8 hint that a beta-turn including T5, N6, Y7 and T8 is a prominent conformational feature in solution. The ring current high field shifts of the methyl group and of the NH of T8 are consistent with an interaction with the side-chain of Y7, favoured by the beta-turn.

Dimethyl Sulfoxide↗
PubMed1987

Synthesis and activity profiles of new dermorphin-(1-4) peptide analogues.

A new series of 12 dermorphin tetrapeptides, W-Tyr-D-MetO-Phe-Xaa-Y (W = H, H2NC = (NH); Xaa = Gly, Sar, D-Ala; Y = OH, OCH3, NH2) were prepared by traditional methods in solution and tested for opioid activity. In binding studies based on displacement of mu, delta, and kappa opioid receptor selective radiolabels from guinea pig brain membranes, the new analogues showed a negligible affinity for the kappa binding site and a preference for mu- over delta-receptors with an evident dependence on N- and/or C-terminal modifications; H-Tyr-D-MetO-Phe-Gly-OCH3 was shown to be one of the most selective mu-receptor ligands reported to date. All these tetrapeptides display dose-related naloxone-reversible antinociceptive effects following intracerebroventricular (icv) or subcutaneous (sc) administrations in mice. In comparison to morphine, H-Tyr-D-MetO-Phe-Sar-NH2 and the guanidino derivative H2NC = (NH)-Tyr-D-MetO-Phe-Gly-NH2 showed lower affinity for mu, delta, and kappa sites but exceptionally stronger analgesia: respectively they are 560 and 1550 times as potent an analgesic as morphine. Among analogues tested after sc administration, H-Tyr-D-MetO-Phe-Sar-NH2 and H-Tyr-D-MetO-Phe-D-Ala-OH displayed the highest activities; they were respectively 22 and 30 times more potent than morphine on a molar basis. These results indicate that N- or C-terminal modifications and substitution at position 2 or 4 of dermorphin-(1-4) peptide do not only influence the affinity of the resulting analogues to opioid receptors but also may favorably alter their pharmacokinetic properties.

Analgesics, Opioid↗
PubMed1987

Opioid peptides. Synthesis and binding assays of desamino-Tyr1 dermorphin analogues. XII.

Eight new dermorphin peptides, X-C6H4-CH2CH2CO-D-Ala-Phe-(L or D)-Yaa-NH2 [X = H, OH; Y = lysine, homoarginine (Har)], were prepared and tested by binding assays. They show negligible affinity for mu-, delta- and K-receptor sites. These findings indicate that the N-terminal ammonium group can not be replaced by the ammonium or guanidinium function located at the side-chain in Lys or Har derivatives.

Analgesics, Opioid↗
PubMed1987

Opioid peptides. Biological study of [D-MetO2] dermorphin analogues in relation to the plurality of opioid receptors. XI.

The opioid activity pattern of 8 dermorphin tetrapeptides, W-Tyr-D-MetO-Phe-Xaa-Y (W = H, H2N-C = (NH); Xaa = Gly, 2-aminoethanol, sarcosine; Y = NH2, NH-alkyl), was determined in guinea-pig ileum (GPI) preparations and in brain binding assays and compared with their antinociceptive potency in mice. Almost all modifications increased potency on the GPI test as well as the antinociceptive action of the parent H-Tyr-D-Ala-Phe-Gly-NH2. Dermorphin, H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2, and related tetrapeptide analogues show negligible K-binding activity and, like morphine, possess a higher affinity to mu- than delta-receptors. Nevertheless the correlation of analgesia with the effects on GPI and binding data separate the peptides from morphine. For example, in comparison with the opiate alkaloid H-Tyr-D-MetO-Phe-Gly-ol and H-Tyr-D-MetO-Phe-Gly-NH2 displayed a lower affinity for mu sites, a moderately higher potency on GPI but an exceptionally stronger analgesia, being respectively 350 and 1500 times as potent an analgesic as morphine. This may involve different subpopulations of opioid mu-receptors.

Animals↗