2. Academic Validation
  3. Improving the selectivity of 3-amidinophenylalanine-derived matriptase inhibitors

Improving the selectivity of 3-amidinophenylalanine-derived matriptase inhibitors

  • Eur J Med Chem. 2022 Aug 5:238:114437. doi: 10.1016/j.ejmech.2022.114437.
Oliver Pilgram 1,  Aline Keils 1,  Gerrit E Benary 1,  Janis Müller 2,  Stefan Merkl 2,  Sandrine Ngaha 1,  Simon Huber 1,  Florent Chevillard 1,  Anne Harbig 3,  Viktor Magdolen 4,  Andreas Heine 1,  Eva Böttcher-Friebertshäuser 3,  Torsten Steinmetzer 5
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, D-35032, Marburg, Germany.
  • 2 CrystalsFirst GmbH, Marbacher Weg 6, D-35032, Marburg, Germany.
  • 3 Institute of Virology, Philipps University, Hans-Meerwein-Str. 2, Marburg, Germany.
  • 4 Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of Munich, Ismaninger Straße 22, D-81675, Munich, Germany.
  • 5 Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, D-35032, Marburg, Germany. Electronic address: steinmetzer@uni-marburg.de.
PMID: 35635944 DOI: 10.1016/j.ejmech.2022.114437
Abstract

A rational structure-based approach was employed to develop novel 3-amidinophenylalanine-derived matriptase inhibitors with improved selectivity against Thrombin and Factor Xa. Of all 23 new derivatives, several monobasic inhibitors exhibit high matriptase affinities and strong selectivity against Thrombin. Some inhibitors also possess selectivity against Factor Xa, although less pronounced as found for Thrombin. A crystal structure of a selective monobasic matriptase inhibitor in complex with matriptase and three crystal structures of related compounds in trypsin and Thrombin have been determined. The structures offer an explanation for the different selectivity profiles of these inhibitors and contribute to a more detailed understanding of the observed structure-activity relationship. Selected compounds were tested in vitro against a matriptase-dependent H9N2 Influenza Virus strain and demonstrated a concentration-dependent inhibition of virus replication in MDCK(II) cells.

Keywords

Antiviral potency; Crystal structure determination; Inhibitor design; Matriptase; Synthesis.

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