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Nienaturalne aminokwasy jako strategia do otrzymywania substratów, inhibitorów i niskocząsteczkowych sond aktywności dla enzymów proteolitycznych

Poręba Marcin, Kasperkiewicz-Wasilewska Paulina, Rut Wioletta, Drąg Marcin

Wiadomości Chemiczne

2022

[Z] 76, 5-6

433--454

Proteolytic enzymes are molecular scissors that are responsible for the amide bond breakdown in peptide and protein substrates. Over the years, the view on proteases has been considerably changed from non-specific digestive enzymes to sophisticated biocatalysts, which by performing limited proteolysis control virtually all biological processes. In order to better understand how proteases work and what are their biologically relevant target substrates, it is indispensable to determine their catalytic preferences. This knowledge can be further utilized to develop selective substrates, inhibitors and activity-based probes (ABPs) enabling the monitoring of proteases activity in various settings, from in vitro analysis on recombinant enzymes or cell lysates to ex vivo and in vivo imaging at the single cell level. Among many chemical-based approaches that have been developed and applied over the years, the Hybrid Combinatorial Substrate Library (HyCoSuL) technology has emerged as one of the most powerful one. HyCoSuL is a combinatorial peptide-based library of fluorogenic substrates, that comprise natural and unnatural amino acids, that can deeply explore the chemical space in proteases active site, providing a structural framework for the development of highly-selective chemical tools. In this review we present the most prominent examples of proteolytic enzymes that have been profiled with HyCoSuL approach yielding selective substrates, potent inhibitors, and very sensitive activity-based probes.

Aminokwasy, glikany, peptydy i białka w ścieżkach diagnostycznych i terapeutycznych chorób cywilizacyjnych XXI wieku : projektowanie i charakterystyka fizykochemiczna oraz strukturalna

Bylińska Irena, Dzierżyńska Maria, Giżyńska Małgorzata, Guzow Katarzyna, Jankowska Elżbieta, Jurczak Przemysław, Kaczyński Zbigniew, Karska Natalia, Kowalczyk Agnieszka, Kuncewicz Katarzyna, Orlikowska Marta, Sawicka Justyna, Spodzieja Marta, Szpakowska Nikola, Szymańska Aneta, Wieczerzak Ewa, Witkowska Julia, Rodziewicz-Motowidło Sylwia

Wiadomości Chemiczne

2022

[Z] 76, 5-6

393--431

The civilization diseases of the 21st century are non-infectious disorders, affecting a large part of modern society. They are associated with the significant development of industry and technology, and hence with environmental pollution and an unhealthy lifestyle. These factors have led to the development of many civilization diseases, which currently include: cardiovascular diseases, respiratory diseases, diabetes, obesity, malignant tumors, gastrointestinal diseases, mental disorders and allergic diseases. The development of technologies, including modern therapies and new drugs, resulted in increase in life expectancy. This creates a global problem of an aging population with an increasing number of diseases of the old age, i.e. dementias. In addition, sedentary lifestyles and changing diets are the reasons why more and more people develop metabolic diseases, as well as neurological and cognitive disorders characterized by progressive damage to nerve cells and dementia. Currently, problem on a global scale is also the growing resistance to existing antimicrobial drugs. Therefore, the scientists face many challenges related to searching for the causes of these diseases, their diagnosis and treatment. Scientific research conducted at the Department of Biomedical Chemistry at the Faculty of Chemistry of the University of Gdańsk is part of this research trend. In this publication, we discuss various research topics with the long-term aim of solving the problems associated with the diseases mentioned above. The following chapters are dedicated to (i) looking for new effective fluorophores with diagnostic and anti-cancer activity; (ii) designing of new compounds with antibacterial and antiviral activity and their synthesis; (iii) investigating the mechanisms of amyloid deposit formation by human cystatin C and possibilities of inhibition of this process; (iv) designing and studies of compounds activating the proteasome with the potential to suppress the development of neurodegenerative diseases; (v) designing peptide fibrils and hydrogels as drug carriers; (vi) searching for peptide inhibitors of immune checkpoint as potential drugs for immunotherapy; (vii) studying the mechanism of action of selected herpesviruses by determining the structure of viral proteins and (viii) studying the composition of natural glycans and glycoconjugates in order to better understand the mechanisms of interaction of bacteria with the environment or with the host.

Proteolityczny kombinat i jego regulatory

Stój J., Karpowicz P.

Wiadomości Chemiczne

2012

[Z] 66, 11-12

1097-1118

One of the proteolytic pathways existing in a cell is ubiquitin- proteasome system (UPS). This highly organized and ATP-dependent system is based on the multifunctional enzyme – the proteasome. Ubiquitin in this pathway plays a role of a tag which marks proteins intended for destruction. Ubiquitylated proteins are recognized and degraded by the 26S proteasome. It consists of a cylindrical-shaped proteolytic core – the proteasome 20S, and attached to it regulatory particles 19S (Fig. 2). The core is composed of four rings, each of them formed by seven subunits. The inner â-rings harbour active sites (in Eukaryota two of each kind: chymotrypsin-like (ChT-L), trypsin-like (T-L) and peptidylglutamyl (PGPH)). The outer, á-rings create a gated channel leading to the catalytic chamber [8]. In a latent proteasome the gate is closed by tightly packed N-terminal residues of á subunits (Fig. 4). Due to such architecture the active sites of the proteasome are not freely available for the substrates. An opening of the gate in physiological conditions occurs after binding the activators such as 11S, 19S or PA200. By catalysing degradation of proteins, the UPS is deeply involved in regulation of cellular physiology. It is also involved in removing of misfolded or damaged proteins and supports the immune system by generating antigenic peptides. Defects in functioning of this proteolytic system play a causal role in the development of a number of diseases, including inflammation, neurodegenerative diseases and various cancers [2–6] what is the reason why the proteasome has become an important therapeutic target. Detailed information about the structure, catalytic activities and mechanisms of functioning of the different proteasome complexes existing in cells is essential to understand their role in organisms as well as to develop new compounds which may find pharmaceutical application.