Development of a GC-376 Based Peptidomimetic PROTAC As a Degrader of 3-Chymotrypsin-like Protease of SARS-CoV-2

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Feb 14

PMID 38352832

Authors

Deborah Grifagni

Elena Lenci

Alessia De Santis

Andrea Orsetti

Carlo Giorgio Barracchia

Filomena Tedesco

Raffaele Bellini Puglielli

Francesca Lucarelli

Angela Lauriola

Michael Assfalg

Francesca Cantini

Vito Calderone

Daniele Guardavaccaro

Andrea Trabocchi

Mariapina DOnofrio

Simone Ciofi-Baffoni

Affiliations

Soon will be listed here.

Abstract

We have applied a proteolysis targeting chimera (PROTAC) technology to obtain a peptidomimetic molecule able to trigger the degradation of SARS-CoV-2 3-chymotrypsin-like protease (3CL). The PROTAC molecule was designed by conjugating a GC-376 based dipeptidyl 3CL ligand to a pomalidomide moiety through a piperazine-piperidine linker. NMR and crystallographic data complemented with enzymatic and cellular studies showed that (i) the dipeptidyl moiety of PROTAC binds to the active site of the dimeric state of SARS-CoV-2 3CL forming a reversible covalent bond with the sulfur atom of catalytic Cys145, (ii) the linker and the pomalidomide cereblon-ligand of PROTAC protrude from the protein, displaying a high degree of flexibility and no interactions with other regions of the protein, and (iii) PROTAC reduces the protein levels of SARS-CoV-2 3CL in cultured cells. This study paves the way for the future applicability of peptidomimetic PROTACs to tackle 3CL-dependent viral infections.

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