Use of Molecular Modeling to Design Selective NTS2 Neurotensin Analogues

Fanelli, Roberto; Floquet, Nicolas; Besserer-Offroy, Élie; Delort, Bartholomé; Vivancos, Mélanie; Longpré, Jean‐Michel; Renault, Pedro; Martinez, Jean; Sarret, Philippe; Cavelier, Florine

doi:10.1021/acs.jmedchem.6b01848

Cited by 21 publications

(34 citation statements)

References 37 publications

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“…As previously observed (Uhl et al, 1977;St-Pierre et al, 1981;Granier et al, 1982;Lugrin et al, 1991;Held et al, 2013;Fanelli et al, 2017), arginine-to-lysine substitutions at positions 8 and 9 (compound 1) or the insertion of the reduced amine bond between those two residues (2) had no major impact on NTS1/NTS2 receptor binding. As already reported (Doulut et al, 1992;Vivet et al, 2000;René et al, 2013;Fanelli et al, 2015), insertion of the TMSAla residue in position 13 (3) was welltolerated by both receptors, with significantly improved affinity at NTS1 (K i = 0.018 nM), when compared to either 1 or to the native NT(8-13) peptide (220-and 80-fold increase, respectively).…”

Section: Impact Of the Peptide Backbone Modifications On Receptor Binsupporting

confidence: 74%

“…Additionally, we synthesized the NT(8-13) derivatives 7 (H-Lys-Lys-Sip-Tyr-Ile-TMSAla-OH) and 8 (H-Lys [CH 2 NH]Lys-Sip-Tyr-Ile-TMSAla-OH), in which both silylated amino acids were inserted. Previous studies have also revealed that substitution of the Tyr 11 residue could provide a handle controlling NT receptor subtype selectivity (Dubuc et al, 1999;Boules et al, 2010;Einsiedel et al, 2011;Held et al, 2013;Fanelli et al, 2017). Accordingly, compound 9 (H-Lys-Lys-Pro-Lys-Ile-Leu-OH), previously reported in Richelson et al (2008), Einsiedel et al (2011), Fanelli et al (2017), and Magafa et al 2019, showed a significant selectivity in favor to NTS2 (NTS2/NTS1 ratio = 25).…”

Section: Design Of the Nt(8-13) Analogsmentioning

confidence: 81%

“…Since a double Arg 8 -Arg 9 substitution with Lys 8 -Lys 9 is welltolerated in terms of binding, this modification in positions 8-9 was preserved in all analogs (Uhl et al, 1977;St-Pierre et al, 1981;Granier et al, 1982). In addition, it has been previously shown that the incorporation of a reduced Lys 8 -Lys 9 pseudopeptide bond in NT(8-13) analogs provides resistance to exonuclease cleavage with no significant influence on their biological activities (Lugrin et al, 1991;Fanelli et al, 2017). Thus, a second subset of NT(8-13) analogs encompassing a reduced amine bond between these two basic residues was prepared ( Table 1).…”

Section: Design Of the Nt(8-13) Analogsmentioning

confidence: 98%

“…The synthesis of all NT(8-13) analogs are detailed in the Supporting Information. Please note that the synthesis of some of these NT(8-13) derivatives have already been published elsewhere: compounds 1, 9, and 11 in Lugrin et al (1991) and Fanelli et al (2017); compound 2 in Fanelli et al (2017) and Lugrin et al (1991); compounds 3 and 5 in Doulut et al (1992), Vivet et al (2000), René et al (2013), and Fanelli et al (2015); and compounds 15 and 16 in Fanelli et al (2015) and Eiselt et al (2019). Briefly, the designed hexapeptides were synthesized in solution starting from Boc-Leu-OMe commercially available, or Boc-TMSAla-OMe, which was previously described following the standard Boc strategy (Fanelli et al, 2015).…”

Section: Peptide Synthesismentioning

confidence: 99%

“…The results are summarized in Table 2 and Figure 1. As indicated in Table 2, the radioligand binding studies on some NT(8-13) analogs, already reported in previous studies (Lugrin et al, 1991;Fanelli et al, 2015Fanelli et al, , 2017Eiselt et al, 2019), were repeated in a same set of experiments for comparison purposes.…”

Section: Impact Of the Peptide Backbone Modifications On Receptor Binmentioning

confidence: 99%

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Insightful Backbone Modifications Preventing Proteolytic Degradation of Neurotensin Analogs Improve NTS1-Induced Protective Hypothermia

et al. 2020

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Therapeutic hypothermia represents a brain-protective strategy for multiple emergency situations, such as stroke or traumatic injury. Neurotensin (NT), which exerts its effects through activation of two G protein-coupled receptors, namely NTS1 and NTS2, induces a strong and long-lasting decrease in core body temperature after its central administration. Growing evidence demonstrates that NTS1 is the receptor subtype mediating the hypothermic action of NT. As such, potent NTS1 agonists designed on the basis of the minimal C-terminal NT(8-13) bioactive fragment have been shown to produce mild hypothermia and exert neuroprotective effects under various clinically relevant conditions. The high susceptibility of NT(8-13) to protease degradation (half-life <2 min) represents, however, a serious limitation for its use in pharmacological therapy. In light of this, we report here a structure-activity relationship study in which pairs of NT(8-13) analogs have been developed, based on the incorporation of a reduced Lys 8-Lys 9 bond. To further stabilize the peptide bonds, a panel of backbone modifications was also inserted along the peptide sequence, including Sip 10 , D-Trp 11 , Dmt 11 , Tle 12 , and TMSAla 13. Our results revealed that the combination of appropriate chemical modifications leads to compounds exhibiting improved resistance to proteolytic cleavages (>24 h; 16). Among them, the NT(8-13) analogs harboring the reduced amine bond combined with the unnatural amino acids TMSAla 13 (4) and Sip 10 (6) or the di-substitution Lys 11-TMSAla 13 (12), D-Trp 11-TMSAla 13 (14), and Dmt 11-Tle 12 (16) produced sustained hypothermic effects (−3 • C for at least 1 h). Importantly, we observed that hypothermia was mainly driven by the increased stability of the NT(8-13) derivatives, instead of the high binding-affinity at NTS1. Altogether, these results reveal the importance of the reduced amine bond in optimizing the metabolic properties of the NT(8-13) peptide and support the development of stable NTS1 agonists as first drug candidate in neuroprotective hypothermia.

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Section: Impact Of the Peptide Backbone Modifications On Receptor Binsupporting

confidence: 74%

Section: Design Of the Nt(8-13) Analogsmentioning

confidence: 81%

Section: Design Of the Nt(8-13) Analogsmentioning

confidence: 98%

Section: Peptide Synthesismentioning

confidence: 99%

Section: Impact Of the Peptide Backbone Modifications On Receptor Binmentioning

confidence: 99%

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Insightful Backbone Modifications Preventing Proteolytic Degradation of Neurotensin Analogs Improve NTS1-Induced Protective Hypothermia

et al. 2020

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Umpolung Ala^B Reagents for the Synthesis of Non‐Proteogenic Amino Acids, Peptides and Proteins**

et al. 2022

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Non-proteogenic amino acids and functionalized peptides are important motifs in modern drug discovery. Here we report that Ala B can serve as universal building blocks in the synthesis of a diverse collection of modified amino acids, peptides, and proteins. First, we develop the synthesis of Ala B from redox-active esters of aspartic acid resulting in a series of β-boronoalanine derivatives. Next, we show that Ala B can be integrated into automated oligopeptide solidphase synthesis. Ala B is compatible with common transformations used in preparative peptide chemistry such as native chemical ligation and radical desulfurization as showcased by total synthesis of Ala B -containing ubiquitin. Furthermore, Ala B reagents participate in Pdcatalyzed reactions, including CÀ C cross-couplings and macrocyclizations. Taken together, Ala B synthons are practical reagents to access modified peptides, proteins, and in the synthesis of cyclic/stapled peptides.Peptides and proteins are important targets in modern drug discovery because of their ease of synthesis, low toxicity, and target selectivity. [1] Native peptides, however, can often show low bioavailability and short lifetimes rendering them suboptimal for clinical applications. [2] To address these challenges, non-proteogenic amino acids (NPAAs), a class of amino acids not encoded in the human genome, emerged as a valuable tool to increase structural diversity and improve pharmacokinetic properties. [3] Several strategies to access NPAAs are known including the Strecker reaction, [4] asymmetric hydrogenation, [5] conjugate addition, [6] biotransformations, [7] photoredox cross-electrophile coupling, [8] CÀ H activation, [9] and phase-transfer alkylation. [10] Access to unnatural surrogates through any of these strategies complements studies on selective modifications of biologics that can be achieved through various handles that can enable downstream functionalizations (Scheme 1A). One promising approach that can avoid competing reactions with innate groups are transformations based on umpolung of reactivity. [11] We recently reported the synthesis and applications of Ala Sn reagents in the form of carbastannatrane 1, [12] a member of a larger group of reagents where alanine's β-carbon is substituted with a metal or metalloid (Scheme 1B). Ala M reagents represent a novel type of synthons that can be engaged in cross-coupling reactions through a reversal of polarity at the β-carbon.From a conceptual standpoint, these reagents can give rise to native as well as unnatural amino acids based on a formal alanine derivatization. Several members of this family are known including organogermanium Ala Ge 2, [13] organoboron Ala B 3, [14] organosilane Ala Si 4 [14l, 15] organozinc Ala Zn 5, [16] organolithium, [14e,g] and organonickel Ala Ni[17] derivatives

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Development of Macrocyclic Neurotensin Receptor Type 2 (NTS2) Opioid‐Free Analgesics

Desgagné,

Chartier,

Lagard

et al. 2024

Angewandte Chemie

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The opioid crisis has highlighted the urgent need to develop non‐opioid alternatives for managing pain, with an effective, safe, and non‐addictive pharmacotherapeutic profile. Using an extensive structure‐activity relationship approach, here we have identified a new series of highly selective neurotensin receptor type 2 (NTS2) macrocyclic compounds that exert potent, opioid‐independent analgesia in various experimental pain models. To our knowledge, the constrained macrocycle in which the Ile12 residue of NT(7‐12) was substituted by cyclopentylalanine, Pro7 and Pro10 were replaced by allyl‐glycine followed by side‐chain to side‐chain cyclization is the most selective analog targeting NTS2 identified to date (Ki 2.9 nM), showing 30,000‐fold selectivity over NTS1. Of particular importance, this macrocyclic analog is also able to potentiate the analgesic effects of morphine in a dose‐ and time‐dependent manner. Exerting complementary analgesic actions via distinct mechanisms of nociceptive transmission, NTS2‐selective macrocycles can therefore be exploited as opioid‐free analgesics or as opioid‐sparing therapeutics, offering superior pain relief with reduced adverse effects to pain patients.

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Use of Molecular Modeling to Design Selective NTS2 Neurotensin Analogues

Cited by 21 publications

References 37 publications

Insightful Backbone Modifications Preventing Proteolytic Degradation of Neurotensin Analogs Improve NTS1-Induced Protective Hypothermia

Insightful Backbone Modifications Preventing Proteolytic Degradation of Neurotensin Analogs Improve NTS1-Induced Protective Hypothermia

Umpolung Ala^B Reagents for the Synthesis of Non‐Proteogenic Amino Acids, Peptides and Proteins**

Development of Macrocyclic Neurotensin Receptor Type 2 (NTS2) Opioid‐Free Analgesics

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Use of Molecular Modeling to Design Selective NTS2 Neurotensin Analogues

Cited by 21 publications

References 37 publications

Insightful Backbone Modifications Preventing Proteolytic Degradation of Neurotensin Analogs Improve NTS1-Induced Protective Hypothermia

Insightful Backbone Modifications Preventing Proteolytic Degradation of Neurotensin Analogs Improve NTS1-Induced Protective Hypothermia

Umpolung AlaB Reagents for the Synthesis of Non‐Proteogenic Amino Acids, Peptides and Proteins**

Development of Macrocyclic Neurotensin Receptor Type 2 (NTS2) Opioid‐Free Analgesics

Contact Info

Product

Resources

About

Umpolung Ala^B Reagents for the Synthesis of Non‐Proteogenic Amino Acids, Peptides and Proteins**