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Abstract: The peptides for-Met-Ser-Phe-OMe 1, for-Met-Cys-Phe-OMe 2, for-Met-Lys-Phe-OMe 3, and for-Met-Tyr-Phe-OMe 4 were synthesized in order to investigate the importance of a hydrophilic side-chain on the residue at position 2 on biological activities of human neutrophils. Our results seem to highlight that this type of substitution does not facilitate good chemotaxis, although it elicits both superoxide anion production and particularly lysozyme release, in some cases even more potent than the parent fMLP-OMe, if the hydrophilicity is associated with steric hindrance. [ABSTRACT FROM AUTHOR]

Human neutrophils can damage the non-immunized K562 cell line when stimulated by phorbol myristate acetate (PMA). The combination of the activation of protein kinase C by phorbol and the increase of free intracellular calcium by ionophore potentiates the lytic reaction. The OKT9- immunized target cells are not able to induce by themselves the lytic response in neutrophils. hut by combining the two signals, the antigenic stimulus and PMA. a high level of cytolytic response is attained. The addition of EGTA does not affect neutrophil cytotoxicity against antibody-coated targets. while it markedly reduced the lytic reaction against non-immunized targets: in contrast, the addition of ECTA together with the ionophore ionomycin completely suppresses the lysis of immunized and non-immunized targets. The treatment of neutrophils with the protein kinase C inhibitor H-7 causes a dose-related inhibition of the lytic functions that is greater on unsensitized K562. Thus the interaction of Fc receptors with immunized targets is required for reaching the maximal cytolysis. The enhanced lytic activity that occurs in the presence of immunized targets is mediated by calcium flux. as detected by using the monoclonal antibody AB8.28 which hinds to FcIII receptors (FcRIII), thus supporting that both signals are involved. [ABSTRACT FROM AUTHOR]

Abstract: for-Met-Ser(Bzl)-Phe-OMe, for-Met-Cys(Bzl)-Phe-OMe, for-Met-Tyr(Bzl)-Phe-OMe and for-Met-Lys(Z)-Phe-OMe were synthesized to investigate the importance of a bulky protecting group on the side-chain of a hydrophilic residue at position 2 on the biological activities of human neutrophils. Our results indicate that these compounds do not trigger a good chemotactic response, which, in any case, is not improved with respect to that induced by the analogs with the unprotected residues. Instead, both superoxide anion production and, particularly, lysozyme release are more efficient. [ABSTRACT FROM AUTHOR]

Abstract: Nociceptin/orphanin FQ (N/OFQ) produces several biological actions by activating the N/OFQ peptide receptor (NOP). It has been previously shown that N/OFQ stimulates leukocyte chemotaxis both in vitro and in vivo. In the present study we investigated the ability of N/OFQ, in comparison with the proinflammatory peptide formyl-Met-Leu-Phe (fMLP), to stimulate human neutrophil and monocyte chemotaxis and the release of lysozyme and superoxide anion (O2 −) production from neutrophils. fMLP stimulated all the leukocyte functions examined. N/OFQ stimulated monocyte (pEC50 12.15) but not neutrophil chemotaxis. The production of O2 − from neutrophils was not affected by N/OFQ while the release of lysozyme was increased in a concentration dependent manner (pEC50 11.00) although the maximal effects evoked by N/OFQ were about half of those of fMLP. The NOP ligands [Arg14, Lys15]N/OFQ, N/OFQ(1-13)NH2, Ro 64-6198, UFP-101 and the opioid antagonist naloxone were used for pharmacologically characterizing the receptor involved in the monocyte chemoattractant action of N/OFQ. [Arg14, Lys15]N/OFQ, N/OFQ(1-13)NH2, and Ro 64-6198 mimicked the action of N/OFQ showing similar maximal effects and the following order of potency: [Arg14, Lys15]N/OFQ (pEC50 13.22)>Ro 64-6198 (pEC50 12.96)>N/OFQ(1-13)NH2 (pEC50 12.67)>N/OFQ (pEC50 12.15). Moreover, the monocyte chemoattractant action of N/OFQ was not modified by naloxone 1μM while antagonized by UFP-101 10μM (pA2 7.00). Thus, the order of potency of agonists and the antagonist selectivity demonstrated that N/OFQ stimulates human monocyte chemotaxis via NOP receptor activation. [Copyright &y& Elsevier]

Abstract: In order to explore the properties of chemotactic N-formylpeptides containing isopeptide bonds within their backbones, a group of lysine-containing analogs of the prototypical chemotactic tripeptide N-formylmethionyl-leucyl-phenylalanine (fMLF) was synthesized. The new analogs were designed by adding to the HCO-Met or Boc-Met residue a dipeptide fragment made up of Lys and Phe residues joined through Lys N[sup α] or N[sup ε] bonds, in all possible combinations. Thus, the following six pairs of tripeptides were synthesized and examined for their bioactivity: RCO-Met-Lys(Z)-Phe-OMe (2a, b), RCO-Met-Lys(Z-Phe)-OMe (3a, b), Z-Lys(RCO-Met)-Phe-OMe (4a, b), Z-Phe-Lys(RCO-Met)-OMe (5a, b), RCO-Met-Phe-Lys(Z)-OMe (6a, b) and Z-Lys(RCO-Met-Phe)-OMe (7a, b), with R=OC(CH[sub 3])[sub 3] and R=H for compounds a and b, respectively. All the new models were characterized fully and their activity (chemotaxis, superoxide anion production and lysozyme release) on human neutrophils determined as agonists (compounds b) and antagonists (compounds a). All N-formyl derivatives 2b-7b are less potent than fMLF-OMe as chemoattractants, but compound 7b exhibits selective activity as superoxide anion producer. Derivatives 2a-7a do not show antagonistic activity towards fMLF induced chemotaxis and O[sub 2][sup -] production, however, all these compounds except 4a antagonize lysozyme release by 60%. [ABSTRACT FROM AUTHOR]

Abstract: In order to further examine the properties of pseudopeptides containing the 2-hydrazonoacyl fragment, two new series of analogs of the prototypical chemotactic N-formyl-tripeptide HCO-Met-Leu-Phe-OMe were designed and synthesized. The first group contains the new fragment as the N-terminal residue and is represented by the N-aryl derivatives p-Cl-C[sub 6]H[sub 4]-NH-N=C(R)-CO-Leu-Phe-OMe (2 and 3) and by the corresponding N-aroyl analogs p-CH[sub 3]-C[sub 6]H[sub 4]-CO-NH-N=C(R)-CO-Leu-Phe-OMe (4). The second group contains the new fragment in place of the central Leu residue and is represented by compounds HCO-Xaa-NH-N=C(R)-CO-Phe-OMe (7a and 7b) where Xaa is Nle and Met, respectively. The conformational and biochemical properties of the new products were examined. [ABSTRACT FROM AUTHOR]

Abstract: We previously reported the structural and biological properties of the C-terminal sequence (REGDPSSSQHLPSTPSSPRV) coded by the rarely expressed exon 26A of human elastin. It assumes a stable type II β-turn structure spanning the REGD sequence and possesses chemotactic and immunological properties. Here the structural characterization of the sequence coded by this exon was completed. Nuclear magnetic resonance and circular dichroism studies on the N-terminal amino acid sequence (GADEGVRRSLSPELREGD) showed the presence of an α-helix within VRRSL and a type II β-turn within SPEL. The smaller peptides GADEGVRRSLSP and LSPELREGD revealed structural features similar to those identified in the parent peptide. No β-turn was found in the REGD sequence of these peptides and no chemotactic activity was detected, thereby demonstrating that this biological activity is conformation dependent. Structural studies on additional peptides such as LREGD, ELREGD and LSPELREGDPSS showed that the presence of a Glu residue two positions before the Arg residue inhibits the β-turn formation in the REGD sequence. [ABSTRACT FROM AUTHOR]

Abstract: In order to obtain chemotactic peptides with selective bioactivity, a new type of structural modification was introduced at the N‐terminal position of HCO‐Nle‐Leu‐Phe‐OMe. Two groups of analogs have been synthesized both containing a N‐terminal residue of the X=C(R)‐CO‐type replacing the native HCO‐NH‐CH(R)‐CO‐. In particular, the A group of pseudopeptides (2a‐d) possesses a N‐terminal oximic fragment (X=HO‐N) and the B group (3a‐d) a formylhydrazone fragment (X=HCO‐NH‐N). These new ligands have been examined for their capacity to induce chemotaxis and other cellular responses such as superoxide anion production and lysozyme release; although significantly active as chemoattractants they have been found to be practically devoid of secretagog activity, thus exhibiting selective behavior. The adopted chemical modification seems extensible in designing a new class of pseudopeptides (hydrazonopeptides) structurally related to both hydrazinopeptides and peptides containing α,β‐unsaturated residues. [ABSTRACT FROM AUTHOR]

Abstract: The formyltetrapeptides for‐Met‐Leu‐Leu‐Phe‐OMe 1, for‐Met‐Leu‐Aib‐Phe‐OMe 2, for‐Met‐Leu‐Ac[sub 6]c‐Phe‐OMe 3, for‐Met‐Leu‐Pro‐Phe‐OMe 4, for‐Met‐Pro‐Pro‐Phe‐OMe 5, for‐Met‐Aib‐Aib‐Phe‐OMe 6, for‐Met‐Pro‐Aib‐Phe‐OMe 7 and for‐Met‐Aib‐Pro‐Phe‐OMe 8 were synthesized and biologically tested on human neutrophils in an attempt to evaluate the specific receptor pocket dimensions and features. Our results indicate that the shift in the Phe residue to the fourth position in these compounds strongly reduces chemotactic response, but is efficacious in triggering superoxide anion production and lysozyme release (order of potency 3 > 2 > 1 > 4 > 6 > 8 > 5 > 7). The potency of the two latter responses correlates well with the affinity data obtained in binding experiments. [ABSTRACT FROM AUTHOR]