Design, synthesis and biological profile of mixed opioid agonist/N-VGCC blocker peptides

Stefanucci, Azzurra; Novellino, Ettore; Macedonio, Giorgia; Dimmito, Marilisa Pia; Mirzaie, Sako; Cardoso, Fernanda C.; Lewis, Richard J.; Zádor, Ferenc; Erdei, Anna; Dvorácskó, Szabolcs; Tömböly, Csaba; Benyhe, Sándor; Pieretti, Stefano; Minosi, Paola; Mollica, Adriano

doi:10.1039/c7nj04969b

Cited by 8 publications

(7 citation statements)

References 24 publications

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“…The synthesis of the novel free C -terminal peptides 1, 2, and 3 was performed by solid-phase peptide synthesis (SPPS) [31,32,33] on Cl-Trt chloride resin (0.1 mmol scales; loading: 1.6 mmol Cl-/g). All amino acids have the Fmoc- N -terminus and the following side-chain protecting groups: tert -butyloxy-carbonyl (Boc) for Lysine and Tryptophan, 2,2,4,6,7-Pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) for Arginine, O- tert -butyl (O t Bu) for Tyrosine, trityl (Trt) for Cysteine.…”

Section: Chemistrymentioning

confidence: 99%

Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening

et al. 2019

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Morphine, oxycodone, fentanyl, and other µ-opioid receptors (MOR) agonists have been used for decades in antinociceptive therapies. However, these drugs are associated with numerous side effects, such as euphoria, addiction, respiratory depression, and adverse gastrointestinal reactions, thus, circumventing these drawbacks is of extensive importance. With the aim of identifying novel peptide ligands endowed with MOR inhibitory activity, we developed a virtual screening protocol, including receptor-based pharmacophore screening, docking studies, and molecular dynamics simulations, which was used to filter an in-house built virtual library of tetrapeptide ligands. The three top-scored compounds were synthesized and subjected to biological evaluation, revealing the identity of a hit compound (peptide 1) endowed with appreciable MOR inverse agonist effect and selectivity over δ-opioid receptors. These results confirmed the reliability of our computational approach and provided a promising starting point for the development of new potent MOR modulators.

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Section: Chemistrymentioning

confidence: 99%

Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening

et al. 2019

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“…Of note, Stefanucci et al have developed mixed opioid agonist/N-VGCC blocker peptides for the treatment of pain. Furthermore, MORs and N-VGCCs are co-localized on pain-modulating neurons in the central nervous system (CNS) [11]. The development of a multi-target molecule combining an opioid pharmacore and an N-VACC blocker may provide synergistic activity and could serve as a therapeutic candidate for the treatment of severe chronic pain.…”

Section: Introductionmentioning

confidence: 99%

Targeting peripheral κ-opioid receptors for the non-addictive treatment of pain

Beck

Dix

2019

Future Drug. Discov.

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Drug addiction to prescription mu-opioid agonists used in the setting of pain is a major public health threat, affecting millions of Americans. Kappa opioid agonists (KOAs) may serve as a possible solution. KOAs have demonstrated indistinguishable analgesic activity relative to mu-opioid agonists in models of acute and chronic pain; however, conventional KOAs suffer from central nervous system-mediated psychoactive side-effects. In this review, we discuss our efforts, as well as other’s efforts, in developing peripherally-restricted kappa opioid agonists with retained or improved efficacy in rodent models of pain. Results indicate that our lead compound JT09 acts as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired central nervous system-mediated side-effects. In this review, we discuss our former results and future directions.

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“…[14][15][16][17] Nowadays, with the deep study of AMPs, rational modification of natural AMPs and de novo designed AMPs have become an important approach for improving the antimicrobial properties of AMPs, 18 including site-directed amino acid substitutions, 19 amino acid end-tagging, 20 and design of linear pseudo-peptides. 21 However, although numerous studies about AMPs as food preservatives have been reported, they still have some drawbacks, including high synthetic cost, poor antimicrobial activity, and a narrow antimicrobial spectrum, which limit their practical applications. [1][2][3][4]22 Therefore, regarding the development of food preservatives, the design of ultra-short AMPs with potent broad-spectrum antimicrobial effects would contribute to further advancing the development of peptide-based food preservatives based on the inherent advantages of AMPs with favorable biodegradability.…”

Section: Introductionmentioning

confidence: 99%

Characterization of simplified nonapeptides with broad-spectrum antimicrobial activities as potential food preservatives, and their antibacterial mechanism

Yang

Wei

et al. 2023

Food Funct.

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Design, synthesis and biological profile of mixed opioid agonist/N-VGCC blocker peptides

Abstract: Novel mixed opioid agonist/N-VGCC blocker peptides, design, synthesis and biological profile.

Cited by 8 publications

References 24 publications

Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening

Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening

Targeting peripheral κ-opioid receptors for the non-addictive treatment of pain

Characterization of simplified nonapeptides with broad-spectrum antimicrobial activities as potential food preservatives, and their antibacterial mechanism

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