Pharmacology of Amphibian Opiate Peptides

Negri, Lucia; Melchiorri, Pietro; Lattanzi, Roberta

doi:10.1016/s0196-9781(00)00295-3

Cited by 53 publications

(40 citation statements)

References 94 publications

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“…We earlier tested several peptides derived of dermorphins and deltorphins (Amiche et al 1998; Lazarus et al 1999; Negri et al 2000). These were, however, unstable and apparently degraded by traces of proteases present in the enzyme preparation (Jilek et al 2005).…”

Section: Resultsmentioning

confidence: 99%

Substrate specificity of a peptidyl-aminoacyl-l/d-isomerase from frog skin

et al. 2011

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In the skin of fire-bellied toads (Bombina species), an aminoacyl-l/d-isomerase activity is present which catalyses the post-translational isomerization of the l- to the d-form of the second residue of its substrate peptides. Previously, this new type of enzyme was studied in some detail and genes potentially coding for similar polypeptides were found to exist in several vertebrate species including man. Here, we present our studies to the substrate specificity of this isomerase using fluorescence-labeled variants of the natural substrate bombinin H with different amino acids at positions 1, 2 or 3. Surprisingly, this enzyme has a rather low selectivity for residues at position 2 where the change of chirality at the alpha-carbon takes place. In contrast, a hydrophobic amino acid at position 1 and a small one at position 3 of the substrate are essential. Interestingly, some peptides containing a Phe at position 3 also were substrates. Furthermore, we investigated the role of the amino-terminus for substrate recognition. In view of the rather broad specificity of the frog isomerase, we made a databank search for potential substrates of such an enzyme. Indeed, numerous peptides of amphibia and mammals were found which fulfill the requirements determined in this study. Expression of isomerases with similar characteristics in other species can therefore be expected to catalyze the formation of peptides containing d-amino acids.Electronic supplementary materialThe online version of this article (doi:10.1007/s00726-011-0890-6) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Substrate specificity of a peptidyl-aminoacyl-l/d-isomerase from frog skin

et al. 2011

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“…The synthesis of SP-BOT has been previously described (15) but to synthesize the Derm-BOT construct required further synthetic steps. Dermorphin is a potent selective opioid mu receptor agonist (31,32,46)and has been successfully used previously in saporin conjugates to selectively ablate MOR-expressing neurons (13). Conjugation of dermorphin to the LcTd portion of botulinum was complicated because dermorphin binds to the receptor through its N-terminus, the portion of the molecule generally used for the botulinum conjugation procedure (16).…”

Section: Discussionmentioning

confidence: 99%

Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice

et al. 2018

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Overline: PainOne Sentence Summary: Silencing key neurons with botulinum toxin conjugates exerts long-lasting pain relief in mouse models of chronic pain. 2 AbstractChronic pain is a widespread debilitating condition affecting millions of people worldwide. Although several pharmacological treatments for relieving chronic pain have been developed, they require frequent chronic administration and are often associated with severe adverse events, including overdose and addiction. Persistent increased sensitization of neuronal subpopulations of the peripheral and central nervous system has been recognized as a central mechanism mediating chronic pain, suggesting that inhibition of specific neuronal subpopulations might produce antinociceptive effects. We leveraged the neurotoxic properties of the botulinum toxin to specifically silence key pain processing neurons in the spinal cords of mice.We show that a single intrathecal injection of botulinum toxin conjugates produced long-lasting pain relief in mouse models of inflammatory and neuropathic pain without toxic side effects. Our results suggest that this strategy might be a safe and effective approach for relieving chronic pain while avoiding the adverse events associated with repeated chronic drug administration.

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“…27, 28 Using the sequence of the frog skin deltorphins26, 29–37 as a template, our laboratory, like others, systematically altered the amino acid sequences in order to deduce the precise functional groups and minimal sequence required for opioid receptor recognition while maintaining or improving δ‐ or μ‐opioid receptor affinity and selectivity 38–40. Although several derivatives with amino acids deleted from the heptapeptide sequences displayed μ‐opioid receptor antagonism,41 the majority of these frog skin derivatives exhibited agonistic behavior that is characteristic of all exogenous amphibian and endogenous vertebrate opioid peptides 28, 42, 43…”

Section: Introductionmentioning

confidence: 99%

Expression of EphB receptors and EphrinB ligands in the developing chick auditory brainstem

Cramer

Karam

Bothwell

et al. 2002

J of Comparative Neurology

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Nucleus magnocellularis (NM) in the avian auditory brainstem receives auditory input from nerve the VIIIth and projects bilaterally to nucleus laminaris (NL). This projection preserves binaural segregation in that ipsilateral NM projects to dorsal dendrites of NL and contralateral NM projects to ventral dendrites of NL. We have begun to examine the molecular signals that influence segregation of inputs onto discrete regions of NL cells. We previously showed that the Eph receptor, EphA4, is expressed selectively in the dorsal NL neuropil from embryonic day (E) 9 to E11, when NM axons grow into the NL neuropil. This asymmetric distribution suggests that EphA4 acts as a guidance molecule during binaural segregation. We report here on the developmental changes in the expression of two other Eph receptors, EphB2 and EphB5, and two ligands, ephrin-B1 and ephrin-B2, in the chick auditory brainstem. These proteins are expressed in the auditory nuclei during the maturation of the NM-NL projection. EphB2, EphB5, and ephrin-B1 are expressed in dorsal and ventral NL neuropil and at the midline of the brainstem at E10-E12. At this age, ephrin-B2, a ligand for EphB receptors and for EphA4, is expressed in NL cell bodies and NM-NL axons. The expression of these proteins diminishs in the posthatch ages examined. These results suggest that several members of the Eph family are involved in maturation of the nuclei and their projections. Moreover, ephrin-B2 in growing axons may interact with the asymmetrically expressed EphA4 during the establishment of binaural segregation.

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Pharmacology of Amphibian Opiate Peptides

Cited by 53 publications

References 94 publications

Substrate specificity of a peptidyl-aminoacyl-l/d-isomerase from frog skin

Substrate specificity of a peptidyl-aminoacyl-l/d-isomerase from frog skin

Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice

Expression of EphB receptors and EphrinB ligands in the developing chick auditory brainstem

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