8okc

From Proteopedia

SARS-CoV2 NSP5 in complex with a GC-376 based peptidomimetic PROTAC

Structural highlights

8okc is a 1 chain structure with sequence from Severe acute respiratory syndrome coronavirus 2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

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(Pro)). The PROTAC molecule was designed by conjugating a GC-376 based dipeptidyl 3CL(Pro) 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(Pro) 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(Pro) in cultured cells. This study paves the way for the future applicability of peptidomimetic PROTACs to tackle 3CL(Pro)-dependent viral infections.

Development of a GC-376 Based Peptidomimetic PROTAC as a Degrader of 3-Chymotrypsin-like Protease of SARS-CoV-2.,Grifagni D, Lenci E, De Santis A, Orsetti A, Barracchia CG, Tedesco F, Bellini Puglielli R, Lucarelli F, Lauriola A, Assfalg M, Cantini F, Calderone V, Guardavaccaro D, Trabocchi A, D'Onofrio M, Ciofi-Baffoni S ACS Med Chem Lett. 2024 Jan 10;15(2):250-257. doi: , 10.1021/acsmedchemlett.3c00498. eCollection 2024 Feb 8. PMID:38352832^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Grifagni D, Lenci E, De Santis A, Orsetti A, Barracchia CG, Tedesco F, Bellini Puglielli R, Lucarelli F, Lauriola A, Assfalg M, Cantini F, Calderone V, Guardavaccaro D, Trabocchi A, D'Onofrio M, Ciofi-Baffoni S. Development of a GC-376 Based Peptidomimetic PROTAC as a Degrader of 3-Chymotrypsin-like Protease of SARS-CoV-2. ACS Med Chem Lett. 2024 Jan 10;15(2):250-257. PMID:38352832 doi:10.1021/acsmedchemlett.3c00498