Faculty

Assist. Prof. Damijan Knez, M. Pharm., Ph. D.

Organisation unit:	Department of Pharmaceutical Chemistry
Job title:	Assistant

CONTACT INFORMATION
Business phone:	+386 1 47 69 562
Business fax:	/
E-mail:	is.jl-inu.aff@zenk.najimad
Room:	room 402 (4th floor), laboratory 406

Research work
	Research projects (co)funded by the Slovenian Research Agency. Member of University of Ljubljana: UL Faculty of Pharmacy Code: Z1-1859 Project: Targeted covalent inhibitors: inhibiting monoamine oxidase through non-catalytic amino-acid residues Period: July 1^st, 2019 - June 30^th, 2021 Range on year: 100 FTE Principal Investigator: DAMIJAN KNEZ (SICRIS) Research Activity: 1.09 - Natural sciences and mathematics / Pharmacy Research Organisation: University of Ljubljana, Faculty of Pharmacy (SICRIS) Researchers: SICRIS Citations for bibliographic records: SICRIS 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. The phases of the project and their realization: The ultimate goals of the Project are: (i) to identify covalent fragments binding to nucleophilic amino acid residues of MAO; (ii) to confirm the covalent mode of inhibition for identified fragments; (iii) to design and synthesize TCIs by adding the covalent warhead to reversible MAO inhibitors, and to explore the effects of substituents attached to fragments on the inhibitory potencies; (iv) to determine the stability, reactivity and selectivity of designed TCIs and covalent fragments – leads; (v) to elucidate the binding pose of the most potent designed TCIs and fragment leads in complex with MAO; and (vi) to establish basic pharmacokinetic parameters and cytotoxicity profile of covalent inhibitors. To achieve this goal, the screening of covalent fragment libraries will be performed. For the hit covalent fragments identified their mode of inhibition will be confirmed by macromolecular X-ray crystallography and/ or MS measurements. Novel targeted covalent inhibitors (TCIs) will be designed based on the hit identified and the structures of known reversible MAO inhibitors, then covalently docked into MAO and synthesized. Chemical space will also be explored for the best performing covalent fragments. Compounds will be evaluated in detail regarding their inhibitory potency, stability, reactivity and selectivity against model enzymes. The most promising covalent inhibitors will be subjected to preliminary pharmacokinetic and toxicological evaluation. The identified covalent inhibitors (both TCIs and improved covalent fragments – leads) will be of paramount scientific importance, as they will serve as a valuable tool for future studies of MAO involvement in disorders, and as potential lead compounds in the permanent battle against neurodegenerative and cardiovascular diseases.

Education:

2004–2008: Grammar School, Ravne na Koroškem
2008–2013: Uniform Master’s Study Programme Pharmacy (Master of Pharmacy), University of Ljubljana
2013–2017: Doctoral Programme Biomedicine, Field: Pharmacy (Ph.D), University of Ljubljana

Academic ranks:

2013–2020 : Assistant in the field of Medicinal Chemistry
2020–: Assistant Professor in the field of Medicinal Chemistry

Employment:

2013: researcher (in collaboration with Lek d.d)
2013–2017: young researcher at the Chair of Pharmaceutical Chemistry Faculty of Pharmacy
2017– : researcher on projects

Teaching activities:

Co-supervisor of students for Master's thesis at Faculty of Pharmacy
Uniform Master’s Study Programme Pharmacy: assistant on practical course Analysis and Control of Active Substances

Projects:

researcher on projects of Slovenian Research Agency (Medicinal Chemistry, drug design)
Principal investigator on Slovenian Research Agency project (1^st July 2019 – 30^th June 2021)

Research:

Structure- and ligand-based drug design
Design and synthesis of monoamine oxidase and butyrylcholinesterase inhibitors
Design and synthesis of multifunctional ligands for neurodegenerative disorders

Prizes and awards, scholarships:

2013: The Faculty of Pharmacy Prešeren Award for research work
2015: Scholarship of French Insititute in Slovenia for research work in France (1 months)
2016: Rector’s award for best innovation of University of Ljubljana
2017: Krka award for doctoral thesis

International research visits:

2015: Institute for Structural Biology IBS, Grenoble, France (supervisor: dr. Jacques-Philippe Colletier), 1 month
2016 in 2017: Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Argentina (supervisor: prof. dr. Mariel Marder), 1 month
2017: University of Pavia, Pavia, Italy (supervisor, prof. dr. Claudia Binda), 2 months

Papers and citations:

556 citations (January 2021, Scopus)
H-index: 16 (January 2021, Scopus)

Top publications:

Knez D et al., J Med Chem, 2020; 63: 1361
Meden A, Knez D et al., Chem Comm, 2019; 55: 3765
Knez D et al., Curr Alzheimer Res, 2019; 16: 801
Knez D et al., Eur J Med Chem, 2018; 156: 598
Košak U, Brus B, Knez D et al., J Med Chem, 2018; 61: 119
Knez D et al., Future Med Chem, 2017; 9: 811
Sosič I, Gobec M, Brus V, Knez D et al., Angew Chem, 2016; 55: 5745

Patents:

Knez D, Sova M, Gobec S. Disubtituted azetidines, pyrrolidines, piperidines and azepanes as inhibitors of monoamine oxidase b for the treatment of neurodegenerative diseases: EP3426634(B1), 2020-01-22, WO2018055096(A1), 2018-03-29.
Brus B, Košak U, Knez D, et al., Disubstituted piperidine derivatives as butyrylcholinesterase inhibitors for use in the treatment of Alzheimer’s: EP3256128(B1), 2018-11-14, US10071964(B2), 2018-09-11.
Sosič I, Gobec M, Brus B, Knez D, et al., Psoralen derivatives as non-peptidic inhibitors of chymotrypsin-like activity of the immunoproteasome: EP3256120(B1), 2018-11-14, WO2016151483(A1), 2016-09-29.

Full Bibliography

Back

Changed: 12. May 2016