title: Evaluating Fmoc-amino acids as selective inhibitors of butyrylcholinesterase.
abstract: Cholinesterases are involved in neuronal signal transduction, and perturbation of function has been implicated in diseases, such as Alzheimer's and Huntington's disease. For the two major classes of cholinesterases, such as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), previous studies reported BChE activity is elevated in patients with Alzheimer's disease, while AChE levels remain the same or decrease. Thus, the development of potent and specific inhibitors of BChE have received much attention as a potential therapeutic in the alleviation of neurodegenerative diseases. In this study, we evaluated amino acid analogs as selective inhibitors of BChE. Amino acid analogs bearing a 9-fluorenylmethyloxycarbonyl (Fmoc) group were tested, as the Fmoc group has structural resemblance to previously described inhibitors. We identified leucine, lysine, and tryptophan analogs bearing the Fmoc group as selective inhibitors of BChE. The Fmoc group contributed to inhibition, as analogs bearing a carboxybenzyl group showed ~tenfold higher values for the inhibition constant (KIvalue). Inclusion of a t-butoxycarbonyl on the side chain of Fmoc tryptophan led to an eightfold lower KIvalue compared to Fmoc tryptophan alone suggesting that modifications of the amino acid side chains may be designed to create inhibitors with higher affinity. Our results identify Fmoc-amino acids as a scaffold upon which to design BChE-specific inhibitors and provide the foundation for further experimental and computational studies to dissect the interactions that contribute to inhibitor binding.
authors: Department of Chemistry and Biochemistry, California State University, Long Beach, 1250 Bellflower Boulevard, Long Beach, CA, 90840-9507, USA.
authors: Jeannette
authors: J
authors: Gonzalez
authors: Department of Chemistry and Biochemistry, California State University, Long Beach, 1250 Bellflower Boulevard, Long Beach, CA, 90840-9507, USA.
authors: Jennifer
authors: J
authors: Ramirez
authors: Department of Chemistry and Biochemistry, California State University, Long Beach, 1250 Bellflower Boulevard, Long Beach, CA, 90840-9507, USA. Jason.schwans@csulb.edu.
authors: Jason P
authors: 0000-0001-8011-3758
authors: JP
authors: Schwans
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology*; D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005449:Fluorenes / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007930:Leucine / Q000737:chemistry; D008239:Lysine / Q000737:chemistry; D011485:Protein Binding; D014364:Tryptophan / Q000737:chemistry
chemical_list: D000596:Amino Acids; D002800:Cholinesterase Inhibitors; D005449:Fluorenes; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D014364:Tryptophan; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D007930:Leucine; D008239:Lysine
keywords: Butyrylcholinesterase; Cholinesterase; Fmoc-amino acid; Inhibition; Tryptophan