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Allosteric inhibition of SARS-CoV-2 3CL protease by colloidal bismuth subcitrate† † Electronic supplementary information (ESI) available. See DOI: 10.1039/d1sc03526f

ABSTRACT: The SARS-CoV-2 3-chymotrypsin-like protease (3CLpro or Mpro) is a key cysteine protease for viral replication and transcription, making it an attractive target for antiviral therapies to combat the COVID-19 disease. Here, we demonstrate that bismuth drug colloidal bismuth subcitrate (CBS) is a potent inhibitor for 3CLpro in vitro and in cellulo. Rather than targeting the cysteine residue at the catalytic site, CBS binds to an allosteric site and results in dissociation of the 3CLpro dimer and proteolytic dysfunction. Our work provides direct evidence that CBS is an allosteric inhibitor of SARS-CoV-2 3CLpro. Colloidal bismuth subcitrate (CBS) is an allosteric inhibitor of 3-chymotrypsin-like protease (3CLpro) in SARS-CoV-2. CBS binding causes dimeric 3CLpro dissociation and proteolytic dysfunction, leading to the suppression of SARS-CoV-2 replication.

SUBMITTER: Tao X

PROVIDER: S-EPMC8565384 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:While the blocking barrier (Ueff) and blocking temperature (TB) for “Dysprocenium” SIMs have been increased beyond liquid N2 temperature, device fabrication of these molecules remains a challenge as low-coordinate Ln3+ complexes are very unstable. Encapsulating the lanthanide ion inside a cage such as a fullerene (called endohedral metallofullerene or EMF) opens up a new avenue leading to several Ln@EMF SMMs. The ab initio CASSCF calculations play a pivotal role in identifying target metal ions and suitable cages in this area. Encouraged by our earlier prediction on Ln2@C79N, which was verified by experiments, here we have undertaken a search to enhance the exchange coupling in this class of molecules beyond the highest reported value. Using DFT and ab initio calculations, we have studied a series of Gd2@C2n (30 ≤ 2n ≤ 80), where an antiferromagnetic JGd⋯Gd of −43 cm−1 was found for a stable Gd2@C38-D3h cage. This extremely large and exceptionally rare 4f⋯4f interaction results from a direct overlap of 4f orbitals due to the confinement effect. In larger cages such as Gd2@C60 and Gd2@C80, the formation of two centre-one-electron (2c-1e−) Gd–Gd bonds is perceived. This results in a radical formation in the fullerene cage leading to its instability. To avoid this, we have studied heterofullerenes where one of the carbon atoms is replaced by a nitrogen atom. Specifically, we have studied Ln2@C59N and Ln2@C79N, where strong delocalisation of the electron yields a mixed valence-like behaviour. This suggests a double-exchange (B) is operational, and CASSCF calculations yield a B value of 434.8 cm−1 and resultant JGd–rad of 869.5 cm−1 for the Gd2@C59N complex. These parameters are found to be two times larger than the world-record J reported for Gd2@C79N. Further ab initio calculations reveal an unprecedented Ucal of 1183 and 1501 cm−1 for Dy2@C59N and Tb2@C59N, respectively. Thus, this study offers strong exchange coupling as criteria for new generation SMMs as the existing idea of enhancing the blocking barrier via crystal field modulation has reached its saturation point. Using ab initio calculations, we have made some robust predictions towards lanthanofullerene SMMs exhibiting remarkable characteristics.

Dataset Information

Allosteric inhibition of SARS-CoV-2 3CL protease by colloidal bismuth subcitrate† † Electronic supplementary information (ESI) available. See DOI: 10.1039/d1sc03526f

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