8CZX

Structure of SARS-CoV-2 3CL protease in complex with the cyclopropane based inhibitor 17d

Summary for 8CZX

• Entry DOI: 10.2210/pdb8czx/pdb
• Descriptor: 3C-like proteinase, [(1~{S},2~{R})-2-[4,4-bis(fluoranyl)cyclohexyl]cyclopropyl]methyl ~{N}-[(2~{S})-1-[[(1~{S},2~{S})-1-[bis(oxidanyl)-oxidanylidene-$l^{5}-sulfanyl]-1-oxidanyl-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]carbamate, [(1~{S},2~{R})-2-[4,4-bis(fluoranyl)cyclohexyl]cyclopropyl]methyl ~{N}-[(2~{S})-1-[[(1~{R},2~{S})-1-[bis(oxidanyl)-oxidanylidene-$l^{5}-sulfanyl]-1-oxidanyl-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]carbamate, ... (5 entities in total)
• Functional Keywords: covid-19, protease, severe acute respiratory syndrome coronavirus 2, sars-cov-2 3cl protease inhhibitors, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 70606.44

Authors

Machen, A.J.,Lovell, S.,Battaile, K.P.,Nguyen, H.N.,Chamandi, S.D.,Picard, H.R.,Madden, T.K.,Thruman, H.A.,Kim, Y.,Groutas, W.C.,Chang, K.O. (deposition date: 2022-05-25, release date: 2022-06-22, Last modification date: 2023-10-25)

Primary citation

Dampalla, C.S.,Nguyen, H.N.,Rathnayake, A.D.,Kim, Y.,Perera, K.D.,Madden, T.K.,Thurman, H.A.,Machen, A.J.,Kashipathy, M.M.,Liu, L.,Battaile, K.P.,Lovell, S.,Chang, K.O.,Groutas, W.C.
Broad-Spectrum Cyclopropane-Based Inhibitors of Coronavirus 3C-like Proteases: Biochemical, Structural, and Virological Studies.
Acs Pharmacol Transl Sci, 6:181-194, 2023

PubMed Abstract: The advent of SARS-CoV-2, the causative agent of COVID-19, and its worldwide impact on global health, have provided the impetus for the development of effective countermeasures that can be deployed against the virus, including vaccines, monoclonal antibodies, and direct-acting antivirals (DAAs). Despite these efforts, the current paucity of DAAs has created an urgent need for the creation of an enhanced and diversified portfolio of broadly acting agents with different mechanisms of action that can effectively abrogate viral infection. SARS-CoV-2 3C-like protease (3CL), an enzyme essential for viral replication, is a validated target for the discovery of SARS-CoV-2 therapeutics. In this report, we describe the structure-guided utilization of the cyclopropane moiety in the design of highly potent inhibitors of SARS-CoV-2 3CL, SARS-CoV-1 3CL, and MERS-CoV 3CL. High-resolution cocrystal structures were used to identify the structural determinants associated with the binding of the inhibitors to the active site of the enzyme and unravel the mechanism of action. Aldehydes and inhibited SARS-CoV-2 replication with EC values of 12 and 11 nM, respectively. Furthermore, the corresponding aldehyde bisulfite adducts and were equipotent with EC values of 13 and 12 nM, respectively. The safety index (SI) values for compounds / and / ranged between 7692 and 9090. Importantly, aldehydes / and bisulfite adducts / potently inhibited MERS-CoV 3CL with IC values of 80 and 120 nM, and 70 and 70 nM, respectively. Likewise, compounds / and / inhibited SARS-CoV-1 with IC values of 960 and 350 nM and 790 and 240 nM, respectively. Taken together, these studies suggest that the inhibitors described herein have low cytotoxicity and high potency and are promising candidates for further development as broad-spectrum direct-acting antivirals against highly pathogenic coronaviruses.

PubMed: 36654747
DOI: 10.1021/acsptsci.2c00206

Experimental method

X-RAY DIFFRACTION (1.65 Å)