Autoren:	Müller, Patrick Zimmer, Collin Frey, Ariane Holzmann, Gideon Weldert, Annabelle Carolin Schirmeister, Tanja
Titel:	Ligand-based design of selective peptidomimetic uPA and TMPRSS2 inhibitors with arg bioisosteres
Online-Publikationsdatum:	15-Mär-2024
Erscheinungsdatum:	2024
Sprache des Dokuments:	Englisch
Zusammenfassung/Abstract:	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.
DDC-Sachgruppe:	540 Chemie 540 Chemistry and allied sciences
Veröffentlichende Institution:	Johannes Gutenberg-Universität Mainz
Organisationseinheit:	FB 09 Chemie, Pharmazie u. Geowissensch.
Veröffentlichungsort:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-10222
Version:	Published version
Publikationstyp:	Zeitschriftenaufsatz
Weitere Angaben zur Dokumentart:	Scientific article
Nutzungsrechte:	CC BY
Informationen zu den Nutzungsrechten:	https://creativecommons.org/licenses/by/4.0/
Zeitschrift:	International journal of molecular sciences 25 3
Seitenzahl oder Artikelnummer:	1375
Verlag:	MDPI
Verlagsort:	Basel
Erscheinungsdatum:	2024
ISSN:	1422-0067
DOI der Originalveröffentlichung:	10.3390/ijms25031375
Enthalten in den Sammlungen:	DFG-491381577-G