Discovery and development of small-molecule inhibitors for ADP-Ribosyl hydrolyzing enzymes
Thesis event information
Date and time of the thesis defence
Place of the thesis defence
L1, Pohjanmaansali, Linnanmaa campus
Topic of the dissertation
Discovery and development of small-molecule inhibitors for ADP-Ribosyl hydrolyzing enzymes
Doctoral candidate
Master of Science Tomi Parviainen
Faculty and unit
University of Oulu Graduate School, Faculty of Technology, Research Unit of Sustainable Chemistry
Subject of study
Chemistry
Opponent
Professor Jari Yli-Kauhaluoma, University of Helsinki
Custos
Docent Juha Heiskanen, University of Oulu
Breaking new ground in enzyme inhibition: Chemical tools for human and viral enzymes
This dissertation reports some of the first known inhibitors for human ARH3 and the Chikungunya virus macrodomain. It also demonstrates, for the first time, that SARS-CoV-2 macrodomain 1 is a druggable target that can be modulated with small molecules to achieve a desired therapeutic effect. These findings highlight previously unexplored therapeutic possibilities within ADP ribosylation biology.
ADP ribosylation is a widely occurring and reversible protein modification found across the tree of life. It influences many cellular functions, including immune defense and DNA repair. The removal of this modification is carried out by macrodomain-containing proteins and ADP-ribosyl hydrolases. For example, at sites of DNA damage, ADP-ribosylation acts as a signal to initiate repair processes, after which the modification must be removed promptly. Some viruses can counteract host immune-related ADP-ribosylation by actively removing this modification. Despite their biological importance, only a limited number of inhibitor molecules are known for enzymes that hydrolyze ADP-ribosylation, even though such compounds can serve as valuable chemical probes.
This dissertation focuses on the discovery and development of inhibitor compounds for three enzymes that catalyze ADP-ribosyl hydrolysis: human ARH3, SARS-CoV-2 macrodomain 1, and the macrodomain of the Chikungunya virus. Potential inhibitors were identified through high-throughput screening using a fluorescence resonance energy transfer-based assay. The properties of these compounds were further optimized using structural analogues obtained from commercial suppliers or synthesized during the research.
The dissertation includes synthesis methods for 62 compounds representing three distinctly different chemical scaffolds. The procedures presented can be applied to develop increasingly effective chemical probes. In addition, the work introduces protein–inhibitor crystal structures determined using protein crystallography, supporting structure-based optimization of these compounds toward future drug candidates.
ADP ribosylation is a widely occurring and reversible protein modification found across the tree of life. It influences many cellular functions, including immune defense and DNA repair. The removal of this modification is carried out by macrodomain-containing proteins and ADP-ribosyl hydrolases. For example, at sites of DNA damage, ADP-ribosylation acts as a signal to initiate repair processes, after which the modification must be removed promptly. Some viruses can counteract host immune-related ADP-ribosylation by actively removing this modification. Despite their biological importance, only a limited number of inhibitor molecules are known for enzymes that hydrolyze ADP-ribosylation, even though such compounds can serve as valuable chemical probes.
This dissertation focuses on the discovery and development of inhibitor compounds for three enzymes that catalyze ADP-ribosyl hydrolysis: human ARH3, SARS-CoV-2 macrodomain 1, and the macrodomain of the Chikungunya virus. Potential inhibitors were identified through high-throughput screening using a fluorescence resonance energy transfer-based assay. The properties of these compounds were further optimized using structural analogues obtained from commercial suppliers or synthesized during the research.
The dissertation includes synthesis methods for 62 compounds representing three distinctly different chemical scaffolds. The procedures presented can be applied to develop increasingly effective chemical probes. In addition, the work introduces protein–inhibitor crystal structures determined using protein crystallography, supporting structure-based optimization of these compounds toward future drug candidates.
Created 23.3.2026 | Updated 23.3.2026