Severo Salvadori

Bio: Severo Salvadori is an academic researcher from University of Ferrara. The author has contributed to research in topics: Nociceptin receptor & Agonist. The author has an hindex of 48, co-authored 234 publications receiving 8744 citations. Previous affiliations of Severo Salvadori include National Institutes of Health & University of Naples Federico II.

Solution structure of the Alzheimer amyloid beta-peptide (1-42) in an apolar microenvironment. Similarity with a virus fusion domain.

Abstract: The major components of neuritic plaques found in Alzheimer disease (AD) are peptides known as amyloid beta-peptides (Abeta), which derive from the proteolitic cleavage of the amyloid precursor proteins. In vitro Abeta may undergo a conformational transition from a soluble form to aggregated, fibrillary beta-sheet structures, which seem to be neurotoxic. Alternatively, it has been suggested that an alpha-helical form can be involved in a process of membrane poration, which would then trigger cellular death. Conformational studies on these peptides in aqueous solution are complicated by their tendency to aggregate, and only recently NMR structures of Abeta-(1-40) and Abeta-(1-42) have been determined in aqueous trifluoroethanol or in SDS micelles. All these studies hint to the presence of two helical regions, connected through a flexible kink, but it proved difficult to determine the length and position of the helical stretches with accuracy and, most of all, to ascertain whether the kink region has a preferred conformation. In the search for a medium which could allow a more accurate structure determination, we performed an exhaustive solvent scan that showed a high propensity of Abeta-(1-42) to adopt helical conformations in aqueous solutions of fluorinated alcohols. The 3D NMR structure of Abeta-(1-42) shows two helical regions encompassing residues 8-25 and 28-38, connected by a regular type I beta-turn. The surprising similarity of this structure, as well as the sequence of the C-terminal moiety, with those of the fusion domain of influenza hemagglutinin suggests a direct mechanism of neurotoxicity.

The Tachykinin Peptide Family

Abstract: The tachykinin peptide family certainly represents one of the largest peptide families described in the animal organism. So far, more than 40 tachykinins have been isolated from invertebrate (insects, worms, and molluscs), protochordate, and vertebrate (skin, gastrointestinal tract, peripheral and central nervous system) tissues. Substance P (SP), first identified by bioassay as early as 1931 but sequenced only in 1971, several years after the elucidation of the structure of eledoisin from molluscan tissues and of physalaemin from amphibian skin, may be considered as a prototype of the tachykinins. Hitherto, as many as 19 tachykinins have been isolated from amphibian integument, and eight additional peptides have been isolated from amphibian gut and brain. Counterparts of skin tachykinins in mammalian tissues are SP, neurokinin A, and neurokinin B. Three main receptor subtypes for the tachykinins have been identified (NK1, NK2, and NK3), but their number is probably destined to increase. It is obvious that the peripheral and central effects of the tachykinins may substantially vary depending on the activation of different receptor subtypes. Matters are further complicated by the frequent capacity of the single tachykinins to bind, although with different affinity, to more receptors. It has been recognized that tachykinins have a variety of effects in physiological and pathological conditions, and there is evidence suggesting intrinsic neuroprotective and neurodegenerative properties of these neuropeptides. This review provides an update on the current body of knowledge regarding tachykinin occurrence and distribution in the animal kingdom, from the lowest invertebrates to man, and the physiological and pharmacological actions of tachykinins outlining the pregnant importance of this large peptide family.

Pharmacology of nociceptin and its receptor: a novel therapeutic target

Abstract: Nociceptin (NC), alias Orphanin FQ, has been recently identified as the endogenous ligand of the opioid receptor-like 1 receptor (OP4). This new NC/OP4 receptor system belongs to the opioid family and has been characterized pharmacologically with functional and binding assays on native (mouse, rat, guinea-pig) and recombinant (human) receptors, by using specific and selective agonists (NC, NC(1–13)NH2) and a pure and competitive antagonist, [Nphe1]NC(1–13)NH2. The similar order of potency of agonists and affinity values of the antagonist indicate that the same receptor is present in the four species. OP4 is expressed in neurons, where it reduces activation of adenylyl cyclase and Ca2+ channels while activating K+ channels in a manner similar to opioids. In this way, OP4 mediates inhibitory effects in the autonomic nervous system, but its activities in the central nervous system can be either similar or opposite to those of opioids. In vivo experiments have demonstrated that NC modulates a variety of biological functions ranging from nociception to food intake, from memory processes to cardiovascular and renal functions, from spontaneous locomotor activity to gastrointestinal motility, from anxiety to the control of neurotransmitter release at peripheral and central sites. These actions have been demonstrated using NC and various pharmacological tools, as antisense oligonucleotides targeting OP4 or the peptide precursor genes, antibodies against NC, an OP4 receptor selective antagonist and with data obtained from animals in which the receptor or the peptide precursor genes were knocked out. These new advances have contributed to better understanding of the pathophysiological role of the NC/OP4 system, and ultimately will help to identify the therapeutic potential of new OP4 receptor ligands.

A new selective antagonist of the nociceptin receptor

Abstract: [Phe1Ψ(CH2-NH)Gly2]NC(1-13)NH2 has been tested in the electrically stimulated guinea pig ileum and mouse vas deferens, two nociceptin sensitive preparations. The new compound showed per se little or no effect in the two tissues, but it displaced to the right the concentration-response curves of nociceptin in a concentration-dependent manner. Schild analyses of the data indicated a competitive type of antagonism and pA2 values of 7.02 and 6.75 in the guinea-pig ileum and the mouse vas deferens, respectively. At 10 μM [Phe1Ψ(CH2-NH)Gly2]NC(1-13)NH2 does not modify either the inhibitory effect of deltorphin I (the selective δ opioid receptor agonist) in the mouse vas deferens or that of dermorphine (the selective μ opioid receptor agonist) in the guinea-pig ileum. The present findings indicate that [Phe1Ψ(CH2-NH)Gly2]NC(1-13)NH2 is a selective antagonist of the nociceptin receptor. British Journal of Pharmacology (1998) 123, 163–165; doi:10.1038/sj.bjp.0701640

Address and message sequences for the nociceptin receptor: a structure-activity study of nociceptin-(1-13)-peptide amide.

Abstract: Nociceptin (NC) and some of its fragments as well as nociceptin-(1-13)-peptide amide [NC- (1-13)-NH2] and a series of its analogues were prepared and tested in the mouse vas deferens in an attempt to identify the sequences involved in the activation (message) and in the binding (address) of nociceptin to its receptor. The NC receptor that inhibits the electrically evoked twitches of the mouse vas deferens was demonstrated to be distinct from the delta opioid receptor, since naloxone and Dmt-Tic-OH (a selective delta opioid receptor antagonist) block the delta opioid receptor but have no effect on the nociceptin receptor. Results from structure-activity experiments suggest that (a) the entire sequence of NC may not be required for full biological activities, since NC(1-13)-NH2 is as active as NC; (b) fragments of NC have however to be amidated as in NC(1-13)-NH2 in order to be protected from degradation by proteases; (c) cationic residues (as Arg8,12, Lys9,13) appear to play a functional role, since their replacement with Ala in the sequence of NC(1-13)-NH2 leads to inactivity; (d) the N-terminal tetrapeptide Phe-Gly-Gly-Phe is essential for activity: its full length and flexibility appear to be required for NC receptor activation and/or occupation; (e) Phe4 and not Phe1 appears to be the residue involved in receptor activation, since the replacement of Phe1 with Leu has no effect, while that of Phe4 leads to inactivity. Results summarized in this paper indicate that the structural requirements of NC for occupation and activation of its receptor are different from that of opioids, particularly delta agonists.

Stability of Protein Pharmaceuticals: An Update

Abstract: In 1989, Manning, Patel, and Borchardt wrote a review of protein stability (Manning et al, Pharm Res 6:903-918, 1989), which has been widely referenced ever since At the time, recombinant protein therapy was still in its infancy This review summarizes the advances that have been made since then regarding protein stabilization and formulation In addition to a discussion of the current understanding of chemical and physical instability, sections are included on stabilization in aqueous solution and the dried state, the use of chemical modification and mutagenesis to improve stability, and the interrelationship between chemical and physical instability