The Opiorphin Analog STR-324 Decreases Sensory Hypersensitivity in a Rat Model of Neuropathic Pain.

Background: Neuropathic pain represents a therapeutic challenge, and treatments with increased efficacy and tolerability still need to be developed. Opiorphin protects endogenous enkephalins from degradation, potentiating enkephalin-dependent analgesia via the activation of opioid pathways. Enkephalins are natural ligands of opioid receptors, with strong affinity for δ-opioid receptors.

STR-324, a Stable Analog of Opiorphin, Causes Analgesia in Postoperative Pain by Activating Endogenous Opioid Receptor-dependent Pathways.

Background: Opiorphin is a naturally occurring potent analgesic human peptide. It protects enkephalins from degradation and inhibits pain perception in various acute pain models via activation of endogenous opioid pathways. However, the efficacy of opiorphin continuous infusion and its chemically stable form, STR-324, in postoperative pain is unknown.

Proteolytically Stable Foldamer Mimics of Host-Defense Peptides with Protective Activities in a Murine Model of Bacterial Infection.

The synthesis of bioinspired unnatural backbones leading to foldamers can provide effective peptide mimics with improved properties in a physiological environment. This approach has been applied to the design of structural mimics of membrane active antimicrobial peptides (AMPs) for which activities in vitro have been reported. Yet activities and pharmacokinetic properties in vivo in animal models have remained largely unexplored.

Influence of polar side chains modifications on the dual enkephalinase inhibitory activity and conformation of human opiorphin, a pain perception related peptide.

The dual inhibitory action of the pain related peptide opiorphin (H-Gln-Arg-Phe-Ser-Arg-OH) against neutral endopeptidase (NEP) and aminopeptidase N (AP-N) was further investigated by a SAR study involving minor modifications on the polar side chains of Arg residues and glycosylation with monosaccharides at Ser. None of them exerted dual or individual inhibitory potency superior than opiorphin. However, the correlations deduced offer further proof for the key role of these residues upon the binding and bioactive conformational stabilization of opiorphin.

Opiorphin highly improves the specific binding and affinity of MERF and MEGY to rat brain opioid receptors.

Endogenously occurring opioid peptides are rapidly metabolized by different ectopeptidases. Human opiorphin is a recently discovered natural inhibitor of the enkephalin-inactivating neutral endopeptidase (NEP) and aminopeptidase-N (AP-N) (Wisner et al., 2006).

Proposed Bioactive Conformations of Opiorphin, an Endogenous Dual APN/NEP Inhibitor.

The conformational profiles for the endogenous peptide Opiorphin and a set of seven analogues exhibiting different inhibitory activities toward human aminopeptidase N (hAPN) and human neprilysin (hNEP) were independently computed to deduce a bioactive conformation that Opiorphin may adopt when binding these two enzymes. The conformational space was thoroughly sampled using an iterative simulated annealing protocol, and a library of low-energy conformers was generated for each peptide. Bioactive Opiorphin conformations fitting our experimental structure-activity relationship data were identified for hAPN and hNEP using computational pairwise comparisons between each of the unique low-energy conformations of Opiorphin and its analogues.

Structure-activity relationship study of opiorphin, a human dual ectopeptidase inhibitor with antinociceptive properties.

Toward developing new potential analgesics, this first structure-activity relationship study of opiorphin (H-Gln-Arg-Phe-Ser-Arg-OH), a human peptide inhibiting enkephalin degradation, was performed. A systematic Ala scanning proved that Phe(3) is a key residue for neprilysin and aminopeptidase N (AP-N) ectoenkephalinase inhibition. A series of Phe(3)-halogenated analogues revealed that halogen bonding based optimization strategies are not applicable to this residue.

Efficacy of chronic antidepressant treatments in a new model of extreme anxiety in rats.

Animal models of anxious disorders found in humans, such as panic disorder and posttraumatic stress disorder, usually include spontaneous and conditioned fear that triggers escape and avoidance behaviors. The development of a panic disorder model with a learned component should increase knowledge of mechanisms involved in anxiety disorders. In our ethological model of extreme anxiety in the rat, forced apnea was combined with cold water vaporization in an inescapable situation.

Reversal of diabetic vasculopathy in a rat model of type 1 diabetes by opiorphin-related peptides.

Diabetes results in a myriad of vascular complications, often referred to as diabetic vasculopathy, which encompasses both microvascular [erectile dysfunction (ED), retinopathy, neuropathy, and nephropathy] and macrovascular complications (hypertension, coronary heart disease, and myocardial infarction). In diabetic animals and patients with ED, there is decreased opiorphin or opiorphin-related gene expression in corporal tissue. Both opiorphin and the rat homologous peptide sialorphin are found circulating in the plasma.

On the terminal homologation of physiologically active peptides as a means of increasing stability in human serum--neurotensin, opiorphin, B27-KK10 epitope, NPY.

The terminal homologation by CH(2) insertion into the peptides mentioned in the title is described. This involves replacement of the N-terminal amino acid residue by a β(2) - and of the C-terminal amino acid residue by a β(3) -homo-amino acid moiety (β(2) hXaa and β(3) hXaa, resp.; Fig.

Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.

In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers.

Human Opiorphin, a natural antinociceptive modulator of opioid-dependent pathways.

Mammalian zinc ectopeptidases play important roles in turning off neural and hormonal peptide signals at the cell surface, notably those processing sensory information. We report here the discovery of a previously uncharacterized physiological inhibitor of enkephalin-inactivating zinc ectopeptidases in humans, which we have named Opiorphin. It is a QRFSR peptide that inhibits two enkephalin-catabolizing ectoenzymes, human neutral ecto-endopeptidase, hNEP (EC 3.

Thiorphan, a neutral endopeptidase inhibitor used for diarrhoea, is neuroprotective in newborn mice.

Excitotoxic damage appears to be a critical factor in the formation of perinatal brain lesions associated with cerebral palsy (CP). When injected into newborn mice, the glutamatergic analogue, ibotenate, produces cortical lesions and white matter cysts that mimic human perinatal brain lesions. Neuropeptides are neuronal activity modulators and could therefore modulate glutamate-induced lesions.

Sialorphin (the mature peptide product of Vcsa1) relaxes corporal smooth muscle tissue and increases erectile function in the ageing rat.

Objective: To determine if the mature peptide product of the Vcsa1 gene, sialorphin, could restore erectile function in ageing rats, and whether these effects are mediated through relaxation of corporal smooth muscle tissue, as we recently reported that Vcsa1 is one of the most down-regulated genes in the corpora of rats in three distinct models of erectile dysfunction, and gene transfer of plasmids expressing Vcsa1 into the corpora of ageing rats restored erectile function.

Materials And Methods: Sialorphin was injected intracorporeally into retired breeder rats, and the effect on the physiology of corporal tissue was analysed by intracorporal/blood pressure (ICP/BP) measurement at different times after injection. In organ-bath studies, the ability of sialorphin (1 microg/mL) to enhance C-type natriuretic peptide (CNP) relaxation of corporal smooth muscle tissue strips was investigated after pre-contraction with 1 microm phenylephrine.

Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity.

Sialorphin is an exocrine and endocrine signaling mediator, which has been identified by a genomic approach. It is synthesized predominantly in the submandibular gland and prostate of adult rats in response to androgen steroids and is released locally and systemically in response to stress. We now demonstrate that the cell surface molecule to which sialorphin binds in vivo in the rat kidney is the membrane-anchored neutral endopeptidase (neprilysin; NEP, EC 3.

Biochemical characterization of proline racemases from the human protozoan parasite Trypanosoma cruzi and definition of putative protein signatures.

Proline racemase catalyzes the interconversion of L- and D-proline enantiomers and has to date been described in only two species. Originally found in the bacterium Clostridium sticklandii, it contains cysteine residues in the active site and does not require co-factors or other known coenzymes. We recently described the first eukaryotic amino acid (proline) racemase, after isolation and cloning of a gene from the pathogenic human parasite Trypanosoma cruzi.