Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure–Activity Relationship Studies

González, Sergio; Dumitrascuta, Maria; Eiselt, E; Louis, Stevany; Kunze, Linda; Blasiol, Annalisa; Vivancos, Mélanie; Previti, Santo; Dewolf, Elke; Martin, Charlotte; Tourwé, Dirk; Cavelier, Florine; Gendron, Louis; Sarret, Philippe; Spetea, Mariana; Ballet, Steven

doi:10.1021/acs.jmedchem.0c01376

Cited by 22 publications

(23 citation statements)

References 59 publications

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“…It could, therefore, be suggested that the impact of NK2 and NK3 pharmacophores on opioid activity will strongly depend on the nature of the opioid pharmacophore. The data suggest that anchorage of any C -terminal appendage to the constrained structure of KGOP01 is more tolerated, which is in line with previous studies [ 19 , 38 , 39 ]. In light of the promising opioid data, the KGOP01-based hybrids were therefore selected for further biological evaluation, and NK2 and NK3 receptor binding assays were performed.…”

Section: Discussionsupporting

confidence: 91%

Harnessing the Anti-Nociceptive Potential of NK2 and NK3 Ligands in the Design of New Multifunctional μ/δ-Opioid Agonist–Neurokinin Antagonist Peptidomimetics

et al. 2021

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Opioid agonists are well-established analgesics, widely prescribed for acute but also chronic pain. However, their efficiency comes with the price of drastically impacting side effects that are inherently linked to their prolonged use. To answer these liabilities, designed multiple ligands (DMLs) offer a promising strategy by co-targeting opioid and non-opioid signaling pathways involved in nociception. Despite being intimately linked to the Substance P (SP)/neurokinin 1 (NK1) system, which is broadly examined for pain treatment, the neurokinin receptors NK2 and NK3 have so far been neglected in such DMLs. Herein, a series of newly designed opioid agonist-NK2 or -NK3 antagonists is reported. A selection of reported peptidic, pseudo-peptidic, and non-peptide neurokinin NK2 and NK3 ligands were covalently linked to the peptidic μ-opioid selective pharmacophore Dmt-DALDA (H-Dmt-d-Arg-Phe-Lys-NH2) and the dual μ/δ opioid agonist H-Dmt-d-Arg-Aba-βAla-NH2 (KGOP01). Opioid binding assays unequivocally demonstrated that only hybrids SBL-OPNK-5, SBL-OPNK-7 and SBL-OPNK-9, bearing the KGOP01 scaffold, conserved nanomolar range μ-opioid receptor (MOR) affinity, and slightly reduced affinity for the δ-opioid receptor (DOR). Moreover, NK binding experiments proved that compounds SBL-OPNK-5, SBL-OPNK-7, and SBL-OPNK-9 exhibited (sub)nanomolar binding affinity for NK2 and NK3, opening promising opportunities for the design of next-generation opioid hybrids.

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Section: Discussionsupporting

confidence: 91%

Harnessing the Anti-Nociceptive Potential of NK2 and NK3 Ligands in the Design of New Multifunctional μ/δ-Opioid Agonist–Neurokinin Antagonist Peptidomimetics

et al. 2021

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“…While the incorporation of an unnatural amino acid could be limited to a substitution, an extensive variety of backbone modifications could be inserted [41,42]. The introduction of peptoids, βand γ-amino acids, azapeptides, N-methylation, and reduced peptide bonds are only some of the common modifications that may be incorporated along the peptide backbone [43][44][45][46][47][48].…”

Section: Introductionmentioning

confidence: 99%

Development of Reduced Peptide Bond Pseudopeptide Michael Acceptors for the Treatment of Human African Trypanosomiasis

et al. 2022

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Human African Trypanosomiasis (HAT) is an endemic protozoan disease widespread in the sub-Saharan region that is caused by T. b. gambiense and T. b. rhodesiense. The development of molecules targeting rhodesain, the main cysteine protease of T. b. rhodesiense, has led to a panel of inhibitors endowed with micro/sub-micromolar activity towards the protozoa. However, whilst impressive binding affinity against rhodesain has been observed, the limited selectivity towards the target still remains a hard challenge for the development of antitrypanosomal agents. In this paper, we report the synthesis, biological evaluation, as well as docking studies of a series of reduced peptide bond pseudopeptide Michael acceptors (SPR10–SPR19) as potential anti-HAT agents. The new molecules show Ki values in the low-micro/sub-micromolar range against rhodesain, coupled with k2nd values between 1314 and 6950 M−1 min−1. With a few exceptions, an appreciable selectivity over human cathepsin L was observed. In in vitro assays against T. b. brucei cultures, SPR16 and SPR18 exhibited single-digit micromolar activity against the protozoa, comparable to those reported for very potent rhodesain inhibitors, while no significant cytotoxicity up to 70 µM towards mammalian cells was observed. The discrepancy between rhodesain inhibition and the antitrypanosomal effect could suggest additional mechanisms of action. The biological characterization of peptide inhibitor SPR34 highlights the essential role played by the reduced bond for the antitrypanosomal effect. Overall, this series of molecules could represent the starting point for further investigations of reduced peptide bond-containing analogs as potential anti-HAT agents

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“…Several groups developed bifunctional analgesics intended to act on two or more receptors involved in pain transmission. In terms of structure, these molecules consist of an opioid agonist (frequently a ligand of the mu opioid receptor) and an agonist that blocks a certain element of pronociceptive system, e.g., neurokinin-1 (NK-1) [ 9 , 10 ] cholecystokinin (CCK) [ 11 , 12 ], neurotensin (NT) [ 13 ], nociceptin (NOP) [ 14 ], and neuropeptide FF (NPFF) [ 15 ] receptors.…”

Section: Introductionmentioning

confidence: 99%

Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores

Witkowska

Godlewska

Osiejuk

et al. 2022

IJMS

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Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.e., an antagonist of the melanocortin-4 receptor. The results of tests in acute and neuropathic pain models of the obtained compounds have shown that the type of linker used to connect pharmacophores had an effect on antinociceptive activity. Peptidomimetics containing longer flexible linkers were very effective at low doses in the neuropathic pain model. To elucidate the effect of linker lengths, two hybrids showing very high activity and two hybrids with lower activity were further tested for affinity for opioid (mu, delta) and melanocortin-4 receptors. Their complexes with the target receptors were also studied by molecular modelling. Our results do not show a simple relationship between linker length and affinity for particular receptor types but suggest that activity in neuropathic pain is related to a proper balance of receptor affinity rather than maximum binding to any or all of the target receptors.

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Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure–Activity Relationship Studies

Cited by 22 publications

References 59 publications

Harnessing the Anti-Nociceptive Potential of NK2 and NK3 Ligands in the Design of New Multifunctional μ/δ-Opioid Agonist–Neurokinin Antagonist Peptidomimetics

Harnessing the Anti-Nociceptive Potential of NK2 and NK3 Ligands in the Design of New Multifunctional μ/δ-Opioid Agonist–Neurokinin Antagonist Peptidomimetics

Development of Reduced Peptide Bond Pseudopeptide Michael Acceptors for the Treatment of Human African Trypanosomiasis

Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores

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