Ligand-Based Design of Selective Peptidomimetic uPA and TMPRSS2 Inhibitors with Arg Bioisosteres.

Publication date: Jan 23, 2024

Trypsin-like serine proteases are involved in many important physiological processes like blood coagulation and remodeling of the extracellular matrix. On the other hand, they are also associated with pathological conditions. The urokinase-pwlasminogen activator (uPA), which is involved in tissue remodeling, can increase the metastatic behavior of various cancer types when overexpressed and dysregulated. Another member of this protease class that received attention during the SARS-CoV 2 pandemic is TMPRSS2. It is a transmembrane serine protease, which enables cell entry of the coronavirus by processing its spike protein. A variety of different inhibitors have been published against both proteases. However, the selectivity over other trypsin-like serine proteases remains a major challenge. In the current study, we replaced the arginine moiety at the P1 site of peptidomimetic inhibitors with different bioisosteres. Enzyme inhibition studies revealed that the phenylguanidine moiety in the P1 site led to strong affinity for TMPRSS2, whereas the cyclohexylguanidine derivate potently inhibited uPA. Both inhibitors exhibited high selectivity over other structurally similar and physiologically important proteases.

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Concepts Keywords
Bioisosteres arginine bioisosteres
Coronavirus covalent reversible inhibitors
Cyclohexylguanidine enzyme inhibition study
Overexpressed peptidomimetic sequence
Remodeling protease inhibitors
trypsin-like serine proteases


Type Source Name
drug DRUGBANK Urokinase
drug DRUGBANK L-Arginine
drug DRUGBANK Trypsin
drug DRUGBANK Serine
disease MESH cancer
disease IDO cell
disease IDO site
drug DRUGBANK Histidine
drug DRUGBANK L-Lysine
disease MESH inflammation
disease IDO virulence
disease MESH infectious diseases
disease VO NS3
disease IDO replication
disease IDO process
drug DRUGBANK Coenzyme M
disease MESH metastasis
drug DRUGBANK Upamostat
disease VO USA
disease IDO host
disease VO Viruses
drug DRUGBANK Angiotensin II
disease MESH SARS CoV 2 infection
drug DRUGBANK Papain
drug DRUGBANK Glycine
drug DRUGBANK L-Threonine
drug DRUGBANK Alpha-Linolenic Acid
drug DRUGBANK L-Asparagine
disease VO protocol
drug DRUGBANK Iodine
drug DRUGBANK Pyrazole
drug DRUGBANK Nitrite
drug DRUGBANK L-Phenylalanine
drug DRUGBANK Carbamazepine
drug DRUGBANK Activated charcoal
drug DRUGBANK Alteplase
drug DRUGBANK Thrombin
drug DRUGBANK Guanidine
drug DRUGBANK Chlorine

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