Recently, a revival of interest in small peptide molecules as potential drug candidates has emerged. In this review, we describe two series of synthetic peptides and their selective effects on the inflammatory response, focusing on the intracellular pathways involved and on their therapeutic potential. A series of FDLFDLF analogs have been synthesized, including either N- t-Boc or different N-ureido substituents. The free acid derivatives are able to antagonize the multiple neutrophil functions evoked by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLF), i.e. chemotaxis, superoxide anion production and lysozyme release, so they are good candidates as anti-inflammatory drugs. Their methyl-ester derivatives are ineffective. The second series of peptides derives from the endogenous protein kinase C (PKC) inhibitor PKI55, a 55-amino acid protein, whose synthesis is induced by PKC activation, so that a feedback loop of inhibition is established. In vitro experiments showed that PKI55 inhibits recombinant PKC isoforms α, β1, β2, γ, δ, ζ, ε; to identify the minimal amino acid sequence of PKI55 protein maintaining the inhibitory effects on PKC, peptides derived from both C- and N-terminal sequences have been synthesized. The N-terminal peptides 5 (MLYKLHDVCRQLWFSC), 8 (CRQLWFSC) and 9 (CRQLW), that in human neutrophils retain the inhibitory activity on PKC, decrease the chemotaxis, and, in mice, display anti-inflammatory and analgesic action, after both central and peripheral administration of very low doses. Furthermore, in a model of cerebral ischemia in vitro, the peptide 5 shows neuroprotective activity, favouring the recovery of synaptic function. These findings suggest interesting possible therapeutic applications for these peptides.
Effects of Synthetic Peptides on the Inflammatory Response and Their Therapeutic Potential.
SELVATICI, Rita;SINISCALCHI, Anna;SPISANI, Susanna
2013
Abstract
Recently, a revival of interest in small peptide molecules as potential drug candidates has emerged. In this review, we describe two series of synthetic peptides and their selective effects on the inflammatory response, focusing on the intracellular pathways involved and on their therapeutic potential. A series of FDLFDLF analogs have been synthesized, including either N- t-Boc or different N-ureido substituents. The free acid derivatives are able to antagonize the multiple neutrophil functions evoked by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLF), i.e. chemotaxis, superoxide anion production and lysozyme release, so they are good candidates as anti-inflammatory drugs. Their methyl-ester derivatives are ineffective. The second series of peptides derives from the endogenous protein kinase C (PKC) inhibitor PKI55, a 55-amino acid protein, whose synthesis is induced by PKC activation, so that a feedback loop of inhibition is established. In vitro experiments showed that PKI55 inhibits recombinant PKC isoforms α, β1, β2, γ, δ, ζ, ε; to identify the minimal amino acid sequence of PKI55 protein maintaining the inhibitory effects on PKC, peptides derived from both C- and N-terminal sequences have been synthesized. The N-terminal peptides 5 (MLYKLHDVCRQLWFSC), 8 (CRQLWFSC) and 9 (CRQLW), that in human neutrophils retain the inhibitory activity on PKC, decrease the chemotaxis, and, in mice, display anti-inflammatory and analgesic action, after both central and peripheral administration of very low doses. Furthermore, in a model of cerebral ischemia in vitro, the peptide 5 shows neuroprotective activity, favouring the recovery of synaptic function. These findings suggest interesting possible therapeutic applications for these peptides.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
