8OKC

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

Summary for 8OKC

• Entry DOI: 10.2210/pdb8okc/pdb
• Related: 7nwx 7nxh 8b0s 8b0t
• Descriptor: 3C-like proteinase nsp5, (phenylmethyl) ~{N}-[(2~{R})-1-[[(~{Z},2~{S})-5-[4-[[1-[2-[(3~{R})-2,6-bis(oxidanylidene)piperidin-3-yl]-6-fluoranyl-1,3-bis(oxidanylidene)isoindol-5-yl]piperidin-4-yl]methyl]piperazin-1-yl]-5-oxidanylidene-1-[(3~{R})-2-oxidanylidenepyrrolidin-3-yl]pent-3-en-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]carbamate (3 entities in total)
• Functional Keywords: nsp5, sars-cov2, 3clpro, protac, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34710.54

Authors

Calderone, V. (deposition date: 2023-03-28, release date: 2024-01-17, Last modification date: 2024-10-09)

Primary citation

Grifagni, D.,Lenci, E.,De Santis, A.,Orsetti, A.,Barracchia, C.G.,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., 15:250-257, 2024

PubMed 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.

PubMed: 38352832
DOI: 10.1021/acsmedchemlett.3c00498

Experimental method

X-RAY DIFFRACTION (2 Å)