2. Academic Validation
  3. Thiazolyl 4-carboxylate ketone as a new warhead for a highly potent SARS-CoV-2 main protease inhibitor

Thiazolyl 4-carboxylate ketone as a new warhead for a highly potent SARS-CoV-2 main protease inhibitor

  • Eur J Med Chem. 2026 Feb 5:303:118436. doi: 10.1016/j.ejmech.2025.118436.
Maria A Theodoropoulou 1,  Haifa El Kilani 2,  Christiana Mantzourani 3,  Dirk Jochmans 4,  Johan Neyts 5,  Kaixuan Zhang 6,  Judith Röske 7,  Maroula G Kokotou 8,  Rolf Hilgenfeld 9,  George Kokotos 10
Affiliations

Affiliations

  • 1 Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, 15771, Athens, Greece; Center of Excellence for Drug Design and Discovery, National and Kapodistrian University of Athens, Panepistimiopolis, 15771, Athens, Greece. Electronic address: martheod@chem.uoa.gr.
  • 2 Institute of Molecular Medicine, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany. Electronic address: haifa.elkilani@uni-luebeck.de.
  • 3 Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, 15771, Athens, Greece; Center of Excellence for Drug Design and Discovery, National and Kapodistrian University of Athens, Panepistimiopolis, 15771, Athens, Greece. Electronic address: chrmantz@chem.uoa.gr.
  • 4 Virology, Antiviral Drug & Vaccine Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium. Electronic address: dirk.jochmans@kuleuven.be.
  • 5 Virology, Antiviral Drug & Vaccine Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium. Electronic address: johan.neyts@kuleuven.be.
  • 6 Institute of Molecular Medicine, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany. Electronic address: kaixuan.zhang@uni-luebeck.de.
  • 7 Institute of Molecular Medicine, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany. Electronic address: judith.roeske@uni-luebeck.de.
  • 8 Laboratory of Chemistry, Department of Food Science and Human Nutrition, Agricultural University of Athens, Iera Odos 75, 11855, Athens, Greece. Electronic address: mkokotou@aua.gr.
  • 9 Institute of Molecular Medicine, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany. Electronic address: rolf.hilgenfeld@uni-luebeck.de.
  • 10 Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, 15771, Athens, Greece; Center of Excellence for Drug Design and Discovery, National and Kapodistrian University of Athens, Panepistimiopolis, 15771, Athens, Greece. Electronic address: gkokotos@chem.uoa.gr.
PMID: 41344111 DOI: 10.1016/j.ejmech.2025.118436
Abstract

The SARS-CoV-2 main protease (Mpro), an enzyme essential for viral replication and lacking a human homologue, has emerged as a highly attractive target for the development of novel Antiviral agents. Although several Mpro inhibitors have been developed - some receiving regulatory approval - their use is sometimes limited by drug-drug interactions. In this study, we designed and synthesized peptidomimetic SARS-CoV-2 Mpro inhibitors incorporating a novel thiazolyl 4-carboxylate ketone warhead, previously employed by our group in the development of cytosolic Phospholipase A2 inhibitors. The synthesized compounds were evaluated for their in vitro inhibitory potency against SARS-CoV-2 Mpro, and a highly potent Mpro inhibitor (GK730) was identified (IC50 5.75 nM). The melting temperature of the Mpro-GK730 complex revealed high stability, consistent with the high inhibitory potency. The X-ray crystal structures of inhibitors GK729 and GK730 bound to Mpro were determined, providing insights into the binding interactions and mechanism of action. Studies on the host cell proteases Cathepsin B and L showed that GK730 did not inhibit Cathepsin B, while exhibited weak inhibition of Cathepsin L. Furthermore, GK730 demonstrated an EC50 value of 5.70 μM against a wild-type SARS-CoV-2 strain in Vero E6 cells and minimal cytotoxicity (CC50 value greater than 100 μM).

Keywords

Inhibitors; Main protease; SARS-CoV-2; Thiazolyl 4-carboxylate ketone warhead; X-ray crystal structure.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-180229
    SARS-CoV 2 型主蛋白酶抑制剂
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z