Introduction of lipidization–cationization motifs affords systemically bioavailable neuropeptide Y and neurotensin analogs with anticonvulsant activities

Abstract

The neuropeptides galanin (GAL), neuropeptide Y (NPY) or neurotensin (NT) exhibit anticonvulsant activities mediated by their respective receptors in the brain. To transform these peptides into potential neurotherapeutics, their systemic bioavailability and metabolic stability must be improved. Our recent studies with GAL analogs suggested that an introduction of lipoamino acids in the context of oligo-Lys residues (lipidization-cationization motif) significantly increases their penetration into the brain, yielding potent antiepileptic compounds. Here, we describe an extension of this strategy to NPY and NT. Rationally designed analogs of NPY and NT containing the lipidization-cationization motif were chemically synthesized and their physicochemical and pharmacological properties were characterized. The analogs NPY-BBB2 and NT-BBB1 exhibited increased serum stability, possessed log D > 1.1, retained high affinities toward their native receptors and produced potent antiseizure activities in animal models of epilepsy following intraperitoneal administration. Our results suggest that the combination of lipidization and cationization may be an effective strategy for improving systemic bioavailability and metabolic stability of various neuroactive peptides.

Generating Orally Active Galanin Analogues with Analgesic Activities

“…[32] The significance of the work presented is that the analogs described herein join the rare class of orally bioavailable peptides that demonstrate antinociceptive activity in vivo. This work also encourages an exploration of other systemically-bioavailable anticonvulsant neuropeptides, such as neuropeptide Y, neurotensin, [33] neuropeptide W, [34] and others, [30] to develop them as orally-active leads for analgesia or epilepsy. We see a potential use for orally-active anticonvulsant neuropeptides as future drugs for postoperative treatment for pain that is an alternative to current opioid-based regiments.…”

Converting Peptides into Drug Leads by Lipidation

“…The two neuropeptides conjugated with cationization-lipidation motif, NPY-BBB2 and NT-BBB1, exhibited potent anticonvulsant activities (less than 1 mg/kg, i.p.) in the 6 Hz epilepsy model [15]. Central insertion of the cationizationlipidation motif into NPW also yielded active anticonvulsant compounds [31].…”

“…Amide Enkephalin [11][12][13], Galanin [14][15][16][17][18], GIP [7,19], GLP-1 (liraglutide) [20], hPP [21], IGF1R JM inhibitor [22], Insulin [23][24][25][26][27][28][29]; Leuteinizing hormone releasing hormone (LHRH) [30], NPW [31], NPY [15], NT [15], RC-160 [32,33], STAT3 [34], Tetragastrin [35][36][37], Thyrotropin releasing hormone (TRH) [28,30,38,39] linear Ester Angiotensin II [40,41], BBI [42][43][44], Desmopressin [45], Ghrelin [2,[46][47][48], Salmon calcitonin (sCT) [49][50][51], TRH [52], Octreotide [53] Fatty acid branched Liraglutid...…”

“…6b) exhibited a remarkable decrease of the opioid receptor binding affinity due to the lipidation on the N-terminus which is critical for maintaining its bioactivity [13]. The strategy of lipidation on a noncritical terminus was applied in the modifications of galanin, NPY and neurotensin (NT) and yielded novel anticonvulsant neuropeptides without losing their receptor binding affinities [14,15]. The lipidated galanin analogues Gal-B1 to Gal-B4 ( Table 2) showed a decreasing binding trend to the human GalR1 receptor (hGalR1) and GalR2 receptor (hGalR2) with the increasing distance between the palmitoyl moiety and the pharmacophore of galanin (pharmacophore: Sar-WTLNSAGYLLGP) [14].…”

Analgesic Neuropeptide W Suppresses Seizures in the Brain Revealed by Rational Repositioning and Peptide Engineering

“…To design such NPW-derived compounds, we employed the lipidizationcationization strategy that was successfully applied toward systemically active analogues of GAL, NT, and NPY (GAL-B2, NT-BBB1, and NPY-BBB2, respectively)- (10,(20)(21)(22)(23). Structures and summary of anticonvulsant and physicochemical properties of GAL-B2, NT-BBB1 and NPY-BBB2 are provided in Figure S2 in the Supporting Information.…”