Research

Targeted covalent inhibitors: inhibiting monoamine oxidase through non-catalytic amino-acid residues

Code:

Z1-1859

Range:

01. July 2019 - 30. June 2021

Range:

0,5 FTE

Leader:

Damijan Knez

Field:

1-09 Natural sciences and Mathematics - Pharmacy

Abstract:

Monoamine oxidase (MAO) is a flavin-dependent enzyme that catalyzes the oxidation of amines, and has an important role in the homeostasis of biogenic and exogenic amines. Two isoforms of MAO (i.e., MAO-A and MAO-B) are present in most mammalian tissues and are distinguished by their sensitivities to acetylenic inhibitors clorgyline and L-deprenyl, and by their substrate specificities. Inhibitors of MAO represent an important element in therapeutic armamentarium of depression, as well as Parkinson’s disease, and are gaining much interest in other neurodegenerative disorders such as Alzheimer’s disease. Several lines of evidence have documented the importance of MAO, especially MAO-A, in the field of cardiovascular diseases. With respect to the important pharmacological relevance of MAO, there is a provision for novel MAO inhibitors to battle the aforementioned disorders. Targeted covalent inhibition is a growing and promising area in drug design offering several advantages, such as gains in potency, improved selectivity and prolonged duration of action. Numerous scaffolds have been described and evaluated as MAO inhibitors. Majority of those inhibit MAO in a reversible manner, and the rest irreversibly by forming a covalent adduct with the FAD cofactor. However, targeting non-catalytic amino acid residues of MAO with covalent inhibitors would represent a novel tactic that has not been addressed before.