Integrated in silico and experimental discovery of trimeric peptide ligands targeting Butyrylcholinesterase

Rudra Palash Mukherjee; Geok-Yong Yow; Samuel Sarakbi; Stefano Menegatti; Patrick V Gurgel; Ruben G Carbonell; Benjamin G Bobay

doi:10.1016/j.compbiolchem.2022.107797

Integrated in silico and experimental discovery of trimeric peptide ligands targeting Butyrylcholinesterase

Comput Biol Chem. 2023 Feb:102:107797. doi: 10.1016/j.compbiolchem.2022.107797. Epub 2022 Nov 29.

Authors

Rudra Palash Mukherjee¹, Geok-Yong Yow², Samuel Sarakbi², Stefano Menegatti¹, Patrick V Gurgel³, Ruben G Carbonell⁴, Benjamin G Bobay⁵

Affiliations

¹ Biomanufacturing Training and Education Center (BTEC), North Carolina State University, Raleigh, NC 27606, USA; Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27606, USA.
² Prometic Bioseparations Ltd, Cambridge CB23 7AJ, UK.
³ Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27606, USA; Prometic Bioseparations Ltd, Cambridge CB23 7AJ, UK.
⁴ Biomanufacturing Training and Education Center (BTEC), North Carolina State University, Raleigh, NC 27606, USA; Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27606, USA; William R. Kenan, Jr. Institute for Engineering, Technology and Science North Carolina State University, Raleigh, NC 27606, USA. Electronic address: ruben@ncsu.edu.
⁵ Duke University NMR Center, Duke University Medical Center, Durham, NC 27710, USA; Department of Biochemistry, Duke University, Durham, NC 27710, USA; Department of Radiology, Duke University, Durham, NC 27710, USA. Electronic address: ben.bobay@duke.edu.

PMID: 36463785
DOI: 10.1016/j.compbiolchem.2022.107797

Abstract

Butyrylcholinesterase (BChE) is recognized as a high value biotherapeutic in the treatment of Alzheimer's disease and drug addiction. This study presents the rational design and screening of an in-silico library of trimeric peptides against BChE and the experimental characterization of peptide ligands for purification. The selected peptides consistently afforded high BChE recovery (> 90 %) and purity, yielding up to a 1000-fold purification factor. This study revealed a marked anti-correlated conformational movement governed by the ionic strength and pH of the aqueous environment, which ultimately controls BChE binding and release during chromatographic purification; and highlighted the role of residues within and allosteric to the catalytic triad of BChE in determining biorecognition, thus providing useful guidance for ligand design and affinity maturation.

Keywords: Acetylcholinesterase; Affinity ligands; Butyrylcholinesterase; Molecular docking; Purification.

MeSH terms

Butyrylcholinesterase* / metabolism
Cholinesterase Inhibitors* / chemistry
Ligands
Molecular Docking Simulation
Peptides

Substances

Butyrylcholinesterase
Cholinesterase Inhibitors
Ligands
Peptides