Identification of c[D-Trp-Phe-β-Ala-β-Ala], the First κ-Opioid Receptor-Specific Negative Allosteric Modulator.

Recently, the fungus secondary metabolite cyclotetrapetide c[Trp-Phe-D-Pro-Phe] (CJ-15,208) and its derivatives deserved some attention for their unusual structure and distinctive in vitro and in vivo activity. These tryptophan-containing noncationic opioid peptides can be truly regarded as versatile picklocks capable of activating all opioid receptors. Intriguingly, minimal modification of the potent κ-opioid receptor (KOR) agonist c[D-Trp-Phe-Gly-β-Ala] () yielded c[D-Trp-Phe-β-Ala-β-Ala] (), the first KOR-specific negative allosteric modulator (NAM) reported to-date.

Peptides inhibiting the assembly of monomeric human l-lactate dehydrogenase into catalytically active homotetramer decrease the synthesis of lactate in cultured cells.

The energetic metabolism of cancer cells relies on a substantial commitment of pyruvate to the catalytic action of lactate-generating dehydrogenases. This coupling mainly depends on lactate dehydrogenase A (LDH-A), which is overexpressed in different types of cancers, and therefore represents an appealing therapeutic target. Taking into account that the activity of LDHs is exclusively exerted by their tetrameric forms, it was recently shown that peptides perturbing the monomers-to-tetramer assembly inhibit human LDH-A (hLDH-A).

Peptide direct growth on poly(acrylic acid)/poly(vinyl alcohol) electrospun fibers coated with branched poly(ethylenimine): A solid-phase approach for scaffolds biofunctionalization.

Due to their resemblance to the fibrillar structure of the extracellular matrix, electrospun nanofibrous meshes are currently used as porous and mechanically stable scaffolds for cell culture. In this study, we propose an innovative methodology for growing peptide sequences directly onto the surface of electrospun nanofibers. To achieve this, electrospun fibers were produced from a poly(acrylic acid)/poly(vinyl alcohol) blend that was thermally crosslinked and subjected to a covalent coating of branched poly(ethylenimine).

Conjecturing about Small-Molecule Agonists and Antagonists of α4β1 Integrin: From Mechanistic Insight to Potential Therapeutic Applications.

Integrins are heterodimeric cell-surface receptors that regulate cell-cell adhesion and cellular functions through bidirectional signaling. On the other hand, anomalous trafficking of integrins is also implicated in severe pathologies as cancer, thrombosis, inflammation, allergies, and multiple sclerosis. For this reason, they are attractive candidates as drug targets.

Design, Pharmacological Characterization, and Molecular Docking of Minimalist Peptidomimetic Antagonists of αβ Integrin.

Integrin receptors mediate cell-cell interactions via the recognition of cell-adhesion glycoproteins, as well as via the interactions of cells with proteins of the extracellular matrix, and upon activation they transduce signals bi-directionally across the cell membrane. In the case of injury, infection, or inflammation, integrins of β and α families participate in the recruitment of leukocytes, a multi-step process initiated by the capturing of rolling leukocytes and terminated by their extravasation. In particular, αβ integrin is deeply involved in leukocyte firm adhesion preceding extravasation.

Design and Pharmacological Characterization of αβ Integrin Cyclopeptide Agonists: Computational Investigation of Ligand Determinants for Agonism versus Antagonism.

αβ integrin is a cell adhesion receptor deeply involved in the migration and accumulation of leukocytes. Therefore, integrin antagonists that inhibit leukocytes recruitment are currently regarded as a therapeutic opportunity for the treatment of inflammatory disorder, including leukocyte-related autoimmune diseases. Recently, it has been suggested that integrin agonists capable to prevent the release of adherent leukocytes might serve as therapeutic agents as well.

Design of κ-Opioid Receptor Agonists for the Development of Potential Treatments of Pain with Reduced Side Effects.

The κ-opioid receptor (KOR) has recently emerged as an alternative therapeutic target for the development of pain medications, without deleterious side effects associated with the μ-opioid receptor (MOR). However, modulation of KOR is currently under investigation for the treatment of depression, mood disorders, psychiatric comorbidity, and specific drug addictions. However, KOR agonists also trigger adverse effects including sedation, dysphoria, and hallucinations.

Synthesis and Antiproliferative Activity against Cancer Cells of Indole-Aryl-Amide Derivatives.

Indoles constitute a large family of heterocyclic compounds widely occurring in nature which are present in a number of bioactive natural and synthetic compounds, including anticancer agents or atypical opioid agonists. As a result, exponential increases in the development of novel methods for the synthesis of indole-containing compounds have been reported in the literature. A series of indole-aryl amide derivatives - containing tryptamine or an indolylacetic acid nucleus were designed, synthesized, and evaluated as opioid ligands.

PacDOCK: A Web Server for Positional Distance-Based and Interaction-Based Analysis of Docking Results.

Molecular docking is a key method for structure-based drug design used to predict the conformations assumed by small drug-like ligands when bound to their target. However, the evaluation of molecular docking studies can be hampered by the lack of a free and easy to use platform for the complete analysis of results obtained by the principal docking programs. To this aim, we developed PacDOCK, a freely available and user-friendly web server that comprises a collection of tools for positional distance-based and interaction-based analysis of docking results, which can be provided in several file formats.

Synthesis, Biological Activity and Molecular Docking of Chimeric Peptides Targeting Opioid and NOP Receptors.

Recently, mixed opioid/NOP agonists came to the spotlight for their favorable functional profiles and promising outcomes in clinical trials as novel analgesics. This study reports on two novel chimeric peptides incorporating the fragment Tyr-c[D-Lys-Phe-Phe]Asp-NH (), a cyclic peptide with high affinity for µ and κ opioid receptors (or MOP and KOP, respectively), conjugated with the peptide Ac-RYYRIK-NH, a known ligand of the nociceptin/orphanin FQ receptor (NOP), yielding RP-170-RYYRIK-NH () and RP-170-Gly-RYYRIK-NH (). In vitro, the chimeric gained affinity for KOP, hence becoming a dual KOP/MOP agonist, while behaved as a mixed MOP/NOP agonist with low nM affinity.

Design of α/β-Hybrid Peptide Ligands of α4β1 Integrin Equipped with a Linkable Side Chain for Chemoselective Biofunctionalization of Microstructured Materials.

Arg-Gly-Asp (RGD)-binding integrins, e.g., αvβ3, αvβ1, αvβ5 integrins, are currently regarded as privileged targets for the delivery of diagnostic and theranostic agents, especially in cancer treatment.

Leukocyte Integrin Antagonists as a Novel Option to Treat Dry Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a complex multifactorial degenerative disease that leads to irreversible blindness. AMD affects the macula, the central part of the retina responsible for sharp central vision. Retinal pigment epithelium (RPE) is the main cellular type affected in dry AMD.

Pharmacological Characterization of µ-Opioid Receptor Agonists with Biased G Protein or β-Arrestin Signaling, and Computational Study of Conformational Changes during Receptor Activation.

In recent years, G protein vs. β-arrestin biased agonism at opioid receptors has been proposed as an opportunity to produce antinociception with reduced adverse effects. However, at present this approach is highly debated, a reason why more information about biased ligands is required.

Linker Hydrophilicity Modulates the Anticancer Activity of RGD-Cryptophycin Conjugates.

Most anticancer agents are hydrophobic and can easily penetrate the tumor cell membrane by passive diffusion. This may impede the development of highly effective and tumor-selective treatment options. A hydrophilic β-glucuronidase-cleavable linker was used to connect the highly potent antimitotic agent cryptophycin-55 glycinate with the α β integrin ligand c(RGDfK).

Integrin-Targeting Peptides for the Design of Functional Cell-Responsive Biomaterials.

Integrins are a family of cell surface receptors crucial to fundamental cellular functions such as adhesion, signaling, and viability, deeply involved in a variety of diseases, including the initiation and progression of cancer, of coronary, inflammatory, or autoimmune diseases. The natural ligands of integrins are glycoproteins expressed on the cell surface or proteins of the extracellular matrix. For this reason, short peptides or peptidomimetic sequences that reproduce the integrin-binding motives have attracted much attention as potential drugs.

Purification from Deinococcus radiodurans of a 66 kDa ABC transporter acting on peptides containing at least 3 amino acids.

Deinococcus radiodurans is a Gram positive bacterium the capability of which to withstand high doses of ionizing radiations is well known. Physiologically speaking, D. radiodurans is a proteolytic prokaryote able to express and secrete quite a number of proteases, and to use amino acids as an energy source.

Integrin-Targeting Dye-Doped PEG-Shell/Silica-Core Nanoparticles Mimicking the Proapoptotic Smac/DIABLO Protein.

Cancer cells demonstrate elevated expression levels of the inhibitor of apoptosis proteins (IAPs), contributing to tumor cell survival, disease progression, chemo-resistance, and poor prognosis. Smac/DIABLO is a mitochondrial protein that promotes apoptosis by neutralizing members of the IAP family. Herein, we describe the preparation and in vitro validation of a synthetic mimic of Smac/DIABLO, based on fluorescent polyethylene glycol (PEG)-coated silica-core nanoparticles (NPs) carrying a Smac/DIABLO-derived pro-apoptotic peptide and a tumor-homing integrin peptide ligand.

Functional Selectivity and Antinociceptive Effects of a Novel KOPr Agonist.

Kappa opioid receptor (KOPr) agonists represent alternative analgesics for their low abuse potential, although relevant adverse effects have limited their clinical use. Functionally selective KOPr agonists may activate, in a pathway-specific manner, G protein-mediated signaling, that produces antinociception, over β-arrestin 2-dependent induction of p38MAPK, which preferentially contributes to adverse effects. Thus, functionally selective KOPr agonists biased toward G protein-coupled intracellular signaling over β-arrestin-2-mediated pathways may be considered candidate therapeutics possibly devoid of many of the typical adverse effects elicited by classic KOPr agonists.

Green synthesis of bioactive oligopeptides promoted by recyclable nanocrystalline hydroxyapatite.

The pharmaceutical industry is showing renewed interest in therapeutic peptides. Unfortunately, the chemical synthesis of peptides remains very expensive and problematic in terms of environmental sustainability. Hence, making peptides 'greener' has become a new front line for the expansion of peptide market.

Could Dissecting the Molecular Framework of β-Lactam Integrin Ligands Enhance Selectivity?

By dissecting the structure of β-lactam-based ligands, a new series of compounds was designed, synthesized, and evaluated toward integrins αβ, αβ, and αβ. New selective ligands with antagonist or agonist activities of cell adhesion in the nanomolar range were obtained. The best agonist molecules induced significant adhesion of SK-MEL-24 cells and Saos-2 cells as a valuable model for osteoblast adhesion.

Novel Ligands Targeting αβ Integrin: Therapeutic Applications and Perspectives.

Among the other members of the adhesion molecules' family, αβ integrin, a heterodimeric receptor, plays a crucial role in inflammatory diseases, cancer development, metastasis and stem cell mobilization or retention. In many cases, its function in pathogenesis is not yet completely understood and investigations on ligand binding and related stabilization of active/inactive conformations still represent an important goal. For this reason, starting from the highlight of αβ functions in human pathologies, we report an overview of synthetic αβ integrin ligands under development as potential therapeutic agents.

Endomorphin-2 analogs containing modified tyrosines: Biological and theoretical investigation of the influence on conformation and pharmacological profile.

New analogs of the endogenous opioid agonist endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH) have been obtained by introducing modified tyrosines at the position 1 of the sequence. For all analogs, the cis/trans conformation ratio about the tyramine-Pro amide bond, lipophilicity, receptor affinities, and functional activities, have been determined. Among the novel derivatives, [Dmt(3'-Cl)]EM-2 (4) stood out for its subnanomolar μ-opioid receptor affinity and potent agonist activity, superior to that of the parent peptide EM-2.

In-Peptide Synthesis of Imidazolidin-2-one Scaffolds, Equippable with Proteinogenic or Taggable/Linkable Side Chains, General Promoters of Unusual Secondary Structures.

Peptidomimetics containing ( S)- or ( R)-imidazolidin-2-one-4-carboxylate (Imi) have been obtained by the expedient in-peptide cyclization of ( S)- or ( R)-α,β-diaminopropionic acid (Dap) residues. These Imi scaffolds behave as proline analogues characterized by a flat structure and a trans-restricted geometry of the preceding peptide bond and induce well-defined secondary structures in a biomimetic environment. While ( S)-Imi peptides adopted a γ'-turn conformation, ( R)-Imi induced the contemporary formation of a γ-turn and a rare 11-membered H-bonded structure in the 2→4 opposite direction of the sequence, identified as a ε-turn.

DS-70, a novel and potent α integrin antagonist, is an effective treatment for experimental allergic conjunctivitis in guinea pigs.

Background And Purpose: Allergic conjunctivitis is an eye inflammation that involves the infiltration of immune cells into the conjunctiva via cell surface-adhesion receptors, such as integrin α β . These receptors interact with adhesion molecules expressed on the conjunctival endothelium and may be a target to treat this disease. We synthesized DS-70, a novel α/β-peptidomimetic α integrin antagonist, to prevent the conjunctival infiltration of immune cells and clinical symptoms in a model of allergic conjunctivitis.

Constraining Endomorphin-1 by β,α-Hybrid Dipeptide/Heterocycle Scaffolds: Identification of a Novel κ-Opioid Receptor Selective Partial Agonist.

Herein we present the expedient synthesis of endomorphin-1 analogues containing stereoisomeric β-homo-Freidinger lactam-like scaffolds ([Amo]EM), and we discuss opioid receptor (OR) affinity, enzymatic stability, functional activity, in vivo antinociceptive effects, and conformational and molecular docking analysis. Hence, H-Tyr-Amo-Trp-PheNH resulted to be a new chemotype of highly stable, selective, partial KOR agonist inducing analgesia, therefore displaying great potential interest as a painkiller possibly with reduced harmful side effects.