Faculty

Assoc. Prof. Damijan Knez, MsPharm., 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 404

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
2020–2025: Assistant Professor in the field of Medicinal Chemistry
2020–2025: Associate 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
2017–2021 : researcher on projects
2021– : assistant

Teaching activities:

Supervisor for master's theses in the study programs Pharmacy and Industrial Pharmacy
Master’s program in Pharmacy: Assistant in practical classes for the subjects Pharmaceutical Chemistry 3 (3^rd year), Drug Analysis and Control (4^th year), and Toxicological Chemistry (4^th year)
Study program S2 Industrial Pharmacy (in English): Lecturer for the subjects Pharmaceutical Chemistry and Drug Analysis

Projects:

researcher on projects of Slovenian Research Agency (Medicinal Chemistry, drug design)
Principal investigator on Slovenian Research Agency project (July 1^st, 2019 – June 30^th, 2021)
Principal investigator in start-up research programme funded by University of Ljubljana: "Abatement of neuroinflammation: advanced approaches targeting caspases 1 and 6 (TargCAS)" (January 1^st, 2024 – December 31^st, 2028)

Research:

Structure- and ligand-based drug design
Design and synthesis of monoamine oxidase and butyrylcholinesterase inhibitors, inhibitors of caspases-1 and -6
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
2024: Special Commendation for Young Higher Education Teachers and Staff (University of Ljubljana)

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
2024: University of Pavia, Pavia, Italy (supervisor, prof. dr. Claudia Binda), 3 months

Papers and citations:

1853 citations (May 2025, Scopus)
H-index: 24 (May 2025, Scopus)

Top publications:

Ferjančič Benetik S, Knez D et al. Pharmacology & Therapeutics, 2024; 264:108748
Knez D et al., Acta Pharmaceutica Sinica B, 2023; 13: 2152
Proj M, Strašek N, Pajk S, Knez D, Sosič I. Bioconjugate Chemistry, 2023; 34: 1271
Proj M, Knez D et al., Drug Discovery Today, 2022; 27: 1733
Knez D et al., Journal of Medicinal Chemistry, 2020; 63: 1361
Knez D et al., European Journal of Medicinal Chemistry, 2018; 156: 598
Košak U, Brus B, Knez D et al., Journal of Medicinal Chemistry, 2018; 61: 119
Sosič I, Gobec M, Brus V, Knez D et al., Angewandte Chemie, 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