Silaproline, a Silicon-Containing Proline Surrogate

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

“…An alanine scan strategy, consisting to replace each amino acid of NT(8-13) with alanine, further supports the functional importance of the isopropyl group of Leu 13 in receptor binding (Henry et al, 1993). The proline at position 10, playing a crucial role for peptide conformation was also replaced by the silylated proline surrogate (Sip), which displays very similar conformational properties that the proline residue (Rémond et al, 2016(Rémond et al, , 2017. The substitution of the γ-carbon by a dimethylsilyl group was found to slightly decrease the binding affinity of 5 at both NT receptors.…”

Pain relief devoid of opioid side effects following central action of a silylated neurotensin analog

“…These results are consistent with the crystal structure of the NTS1-NT(8-13) complex in its activatedlike conformation, which shows a tight oriented hydrophobic binding site for the pyrrolidine ring of Pro 10 as well as extensive van der Waals interactions with the residue W339 in ECL3 (Krumm et al, 2016;White et al, 2012). Here, we have therefore replaced Pro 10 by a silylated proline surrogate that exhibits very similar conformational properties that the proline residue in peptides (Remond et al, 2016(Remond et al, , 2017. The substitution of the γ-carbon by a dimethylsilyl group was found to slightly decrease the affinity of JMV2009 for NTS1 while this chemical substitution seemed to be adequate for NTS2 binding.…”

“…Herein, we report the synthesis and in vitro/in vivo characterization of a new NT(8-13) analog, named JMV2009, which binds to both NTS1 and NTS2 receptors. In this compound, the Pro 10 residue was substituted by a silicon-containing unnatural amino acid proline surrogate, denoted silaproline (Sip), which has been shown to retain peptide conformation (Cavelier et al, 2006;Cavelier et al, 2002;Remond et al, 2017;Vivet et al, 2000). This Sip-containing NT(8-13) analog was further screened in a battery of pain models to assess its putative analgesic properties and evaluate for its ability to induce adverse effects associated with chronic opioid therapy, such as constipation or analgesic tolerance.…”

Silicon-Containing Neurotensin Analogues as Radiopharmaceuticals for NTS1-Positive Tumors Imaging

“…Engineered peptides often feature improved biological properties . For example, introduction of unnatural amino acids brings resistance to proteolysis, while allowing the modulation of physicochemical properties thanks to the wide variety of side chains. , Silicon/carbon switch is reported in drug design to provide lipophilicity when carbon atom is replaced with silicon: only with this difference are log D values slightly higher in silicon-containing derivatives. − Incorporation of silicon-containing amino acids in bioactive peptides, − as we already reported for NT[8–13], increases both binding affinity and resistance toward enzyme degradation. , …”

“…[19][20] Silicon/Carbon switch is reported in drug design to provide lipophilicity when carbon atom is replaced with silicon: only with this difference, logD values are slightly higher in silicon-containing derivatives. [21][22][23][24] Incorporation of silicon-containing amino acids in bioactive peptides, [25][26][27][28][29][30] as we already reported for NT [8][9][10][11][12][13], increases both binding affinity and resistance towards enzyme degradation. [31][32] Herein, we describe the synthesis of bioconjugates based on stabilized NT [8][9][10][11][12][13] analogues radiolabeled with 68 Ga using a DOTA macrocycle complex chelator.…”