Synthesis and Applications of Polyamine Amino Acid Residues: Improving the Bioactivity of an Analgesic Neuropeptide, Neurotensin

Abstract

Conjugated polyamines are potential carriers for biotherapeutics targeting the central nervous system. We describe an efficient synthesis of a polyamine-based amino acid, Lysine-trimethylene(diNosyl)-spermine(triBoc) with Dde or Fmoc orthogonal protecting groups. This nonnatural amino acid was incorporated into a neurotensin analogue using standard Fmoc-based protocols. The analogue maintained high affinity and agonist potency for neurotensin receptors and exhibited dramatically improved analgesia in mice. Our work provides a basis for use of polyamine amino acids in polypeptides.

Converting Peptides into Drug Leads by Lipidation

“…Building blocks such as N ε -acyl-Lys and LAA can be chemically synthesized and directly coupled on resin by the Fmoc solid phase peptide synthesis (SPPS) method [18,[159][160][161]. S-Acylated cysteine is not recommended due to possible aminolysis by the α -amino group [162].…”

“…Fmoc-orthogonal protecting groups for the side chain of lysine can be selected from Dde-, Nosyl-, Alloc-, Mtt-and Mmt [163]. Dde group can be deprotected with hydrazine or NH 2 OH· HCl/imidazole in NMP/CH 2 Cl 2 [161,164,165]. Nosyl group can be deprotected with p-methoxythiophenol/K 2 CO 3 in CH 3 CN/ DMSO [166,167].…”

Untitled

“…76 Polyamines can interact with several intracellular targets, including nucleic acids and enzymes, and exert several selective and complex actions on a variety of ion channels. 77,78 Among them, especially remarkable is the dual modulation of aamino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) 79 and N-methyl-D-aspartate (NMDA) receptors 80 , which have been implicated in important plasticity events, such as learning and memory. [81][82][83][84][85][86][87] Polyamines (125-250 nmol, i.c.v.)…”

Quaternary Alkylammonium Conjugates of Steroids: Synthesis, Molecular Structure, and Biological Studies

“…Another class of compounds that are involved in many biological processes are polyamines (spermidine, spermine, putrescine, cadaverine) [7][8][9][10]. Some of these are very important plant hormones and coenzymes.…”