Novel inhibitors and activity-based probes targeting serine proteases

Ferguson, Timothy; Reihill, James; Martin, S. Lorraine; Walker, Brian

doi:10.3389/fchem.2022.1006618

Cited by 3 publications

(2 citation statements)

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“…The specific set of proteases involved in cancer progression, along with their regulators, is known as the cancer degradome, and its components are secreted by both cancer and stromal cells ( 15 ). Serine proteases, including plasmin and PAS components, are an important constituent of cancer degradome ( 24 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of proteolytic activity and serine proteases distribution in plasma from patients with bladder cancer

Synelnyk,

Vovk,

Halenova

et al. 2023

Front. Med.

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BackgroundBladder cancer (BC) is an aggressive disease with a poor prognosis. A bladder tumor, like other malignant neoplasms, is characterized by the presence of both cancer cells and stromal cells which secrete cytokines, chemokines, growth factors, and proteolytic enzymes. One such class of proteolytic enzymes are serine proteases, which take part in the tumor microenvironment formation via supporting and contributing to tumor progression. This study aims to evaluate the proteolytic activity and serine protease contribution in plasma from BC patients.MethodsThe research involved patients of Alexandrovsky city clinical hospital aged 52–76 with transitional cell carcinoma of the bladder. All examined patients were divided into five groups: the control group included conditionally healthy donors, while other patients were grouped according to their tumor stage (I, II, III and IV). Plasma plasminogen levels were determined by enzyme-linked immunosorbent assay, and the potential activity was measured by chromogenic plasminogen assay. Serine proteases fractions were obtained by the affinity chromatography method, and enzyme concentration in the selected fractions were determined by the Bradford method. Serine proteases distribution was investigated by electrophoresis in a polyacrylamide gel.ResultsIt was determined that the concentration, potential activity of plasminogen, and the total amount of serine proteases in plasma from BC patients were greater than the values of the corresponding indicators in healthy donors. This could be one of the factors contributing to increased proteolysis seen in the process of carcinogenesis. Plasminogen concentration in BC patients with stage IV disease; however, displayed a tendency to be reduced compared to earlier stages, and the potential activity of plasminogen was significantly lower in patients with stages III – IV BC. Futhermore, a tumor stage specific gradual decline in the serine protease plasma content was shown. The results of electrophoretic analysis established a significant diminishment in the percentage of high molecular weight components (under non-reducing conditions) and their complete disappearance (under reducing conditions) in plasma serine protease fractions from BC patients. A decline in the percentage of heavy and light plasmin chains in BC patients was also observed. Additionally, a rise in the degraded forms of plasminogen/plasmin content was seen in BC samples, as well as the presence of fractions corresponding to trypsin and NE (under non-reducing conditions) that were absent in the control samples.ConclusionThe results indicate significant changes in the proteolytic activity of plasma, from BC patients when compared to healthy controls, which is accompanied by alterations in serine protease distribution caused by tumor microenvironment pecularlities at the different stages of oncopathology.

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Section: Discussionmentioning

confidence: 99%

Evaluation of proteolytic activity and serine proteases distribution in plasma from patients with bladder cancer

Synelnyk,

Vovk,

Halenova

et al. 2023

Front. Med.

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“…HAI-1 and HAI-2 act in the tumor pericellular microenvironment to block cell signaling by preventing the ligandbased activation of MET and/or RON receptor tyrosine kinases. Thus, potent and selective small molecule inhibitors of each HGF-activating protease can serve as valuable chemical tools, such as activity-based probes (Ferguson et al, 2022;Lourenço, 2023;Sotiropoulou et al, 2022), for studying the distinct roles of HGFA, matriptase and hepsin in cancer and other diseases.…”

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confidence: 99%

Use of protease substrate specificity screening in the rational design of selective protease inhibitors with unnatural amino acids: Application to HGFA, matriptase, and hepsin

Mahoney,

Helander,

Kooner

et al. 2024

Protein Science

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Inhibition of the proteolytic processing of hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) is an attractive approach for the drug discovery of novel anticancer therapeutics which prevent tumor progression and metastasis. Here, we utilized an improved and expanded version of positional scanning of substrate combinatorial libraries (PS‐SCL) technique called HyCoSuL to optimize peptidomimetic inhibitors of the HGF/MSP activating serine proteases, HGFA, matriptase, and hepsin. These inhibitors have an electrophilic ketone serine trapping warhead and thus form a reversible covalent bond to the protease. We demonstrate that by varying the P2, P3, and P4 positions of the inhibitor with unnatural amino acids based on the protease substrate preferences learned from HyCoSuL, we can predictably modify the potency and selectivity of the inhibitor. We identified the tetrapeptide JH‐1144 (8) as a single digit nM inhibitor of HGFA, matriptase and hepsin with excellent selectivity over Factor Xa and thrombin. These unnatural peptides have increased metabolic stability relative to natural peptides of similar structure. The tripeptide inhibitor PK‐1‐89 (2) has excellent pharmacokinetics in mice with good compound exposure out to 24 h. In addition, we obtained an X‐ray structure of the inhibitor MM1132 (15) bound to matriptase revealing an interesting binding conformation useful for future inhibitor design.

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Covalent activity-based probes for imaging of serine proteases

Skorenski,

Ji,

Verhelst

2024

Biochemical Society Transactions

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Serine proteases are one of the largest mechanistic classes of proteases. They regulate a plethora of biochemical pathways inside and outside the cell. Aberrant serine protease activity leads to a wide variety of human diseases. Reagents to visualize these activities can be used to gain insight into the biological roles of serine proteases. Moreover, they may find future use for the detection of serine proteases as biomarkers. In this review, we discuss small molecule tools to image serine protease activity. Specifically, we outline different covalent activity-based probes and their selectivity against various serine protease targets. We also describe their application in several imaging methods.

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Novel inhibitors and activity-based probes targeting serine proteases

Cited by 3 publications

References 87 publications

Evaluation of proteolytic activity and serine proteases distribution in plasma from patients with bladder cancer

Evaluation of proteolytic activity and serine proteases distribution in plasma from patients with bladder cancer

Use of protease substrate specificity screening in the rational design of selective protease inhibitors with unnatural amino acids: Application to HGFA, matriptase, and hepsin

Covalent activity-based probes for imaging of serine proteases

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