Targeting the Main Protease (Mpro, nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies

Nadide Altincekic (Korresp. Autor*in), Nathalie Jores, Frank Löhr, Christian Richter, Claus Ehrhardt, Marcel J J Blommers, Hannes Berg, Sare Öztürk, Santosh L Gande, Verena Linhard, Julien Orts, Marie Jose Abi Saad, Matthias Bütikofer, Janina Kaderli, B Göran Karlsson, Ulrika Brath, Mattias Hedenström, Uwe H Sauer, Anastassis Perrakis, Julian LangerLucia Banci, Francesca Cantini, Marco Fragai, Deborah Grifagni, Tatjana Barthel, Jan Wollenhaupt, Angus Robertson, Adriaan Bax, Sridhar Sreeramulu, Harald Schwalbe (Korresp. Autor*in)

Veröffentlichungen: Beitrag in FachzeitschriftArtikelPeer Reviewed

Abstract

The main protease Mpro, nsp5, of SARS-CoV-2 (SCoV2) is one of its most attractive drug targets. Here, we report primary screening data using nuclear magnetic resonance spectroscopy (NMR) of four different libraries and detailed follow-up synthesis on the promising uracil-containing fragment Z604 derived from these libraries. Z604 shows time-dependent binding. Its inhibitory effect is sensitive to reducing conditions. Starting with Z604, we synthesized and characterized 13 compounds designed by fragment growth strategies. Each compound was characterized by NMR and/or activity assays to investigate their interaction with Mpro. These investigations resulted in the four-armed compound 35b that binds directly to Mpro. 35b could be cocrystallized with Mpro revealing its noncovalent binding mode, which fills all four active site subpockets. Herein, we describe the NMR-derived fragment-to-hit pipeline and its application for the development of promising starting points for inhibitors of the main protease of SCoV2.

OriginalspracheEnglisch
Seiten (von - bis)563-574
Seitenumfang12
FachzeitschriftACS Chemical Biology
Jahrgang19
Ausgabenummer2
Frühes Online-Datum17 Jan. 2024
DOIs
PublikationsstatusVeröffentlicht - 16 Feb. 2024

ÖFOS 2012

  • 106006 Biophysik
  • 104026 Spektroskopie
  • 301207 Pharmazeutische Chemie

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