Functional map of SARS-CoV-2 3CL protease reveals tolerant and immutable sites

Iketani, Sho; Hong, Seo Jung; Sheng, Jenny; Bahari, Farideh; Culbertson, Bruce; Atanaki, Fereshteh Fallah; Aditham, Arjun K.; Kratz, Alexander; Luck, Maria I; Tian, Ruxiao; Goff, Stephen P.; Montazeri, Hesam; Sabo, Yosef; Ho, David D.; Chavez, Alejandro

doi:10.1016/j.chom.2022.08.003

Cited by 44 publications

(44 citation statements)

References 70 publications

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“…Nirmatrelvir key interactions with M pro include hydrogen bounds with H163, E166 and Q189. A recent study used deep mutational scanning to map the mutational landscape of M pro , and found that M49, N142, E166, P168, Q189 and A191 residues have high flexibility, overlapping with most of our chosen residues based on real world data, and found that mutant E166V to be highly resistant to nirmatrelvir ( 23 ). In another recent pre-publication, the authors used a similar approach to ours to identify 11 mutants resistant to nirmatrelvir, including S144M/F/A/G/Y, M165T, E166Q, H172Q/F, and Q192T/S/V ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

Structural basis of nirmatrelvir and ensitrelvir activity against naturally occurring polymorphisms of the SARS-CoV-2 main protease

Noske¹,

Silva²,

Godoy³

et al. 2023

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Structural basis of nirmatrelvir and ensitrelvir activity against naturally occurring polymorphisms of the SARS-CoV-2 main protease

Noske¹,

Silva²,

Godoy³

et al. 2023

Journal of Biological Chemistry

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“…In essence, we treat natural evolution as a deep mutational scan, with the millions of publicly available SARS-CoV-2 sequences providing a readout of this experiment. The key is simply to calculate how many times each mutation has been "tested" along the history Figure 4 Correlation of mutation-effect estimates with experimental deep mutational scanning measurements for (A) the full spike [9] or its RBD [45], and (B) Mpro [21,22]. Each point is an amino-acid mutation, the orange line is a least-squares regression, and orange text in the upper left shows the number of mutations and Pearson correlation coefficient.…”

Section: Discussionmentioning

confidence: 99%

Fitness effects of mutations to SARS-CoV-2 proteins

Bloom

Neher

2023

Preprint

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Knowledge of the fitness effects of mutations to SARS-CoV-2 can inform assessment of new variants, design of therapeutics resistant to escape, and understanding of the functions of viral proteins. However, experimentally measuring effects of mutations is challenging: we lack tractable lab assays for many SARS-CoV-2 proteins, and comprehensive deep mutational scanning has been applied to only two SARS-CoV-2 proteins. Here we develop an approach that leverages millions of publicly available SARS-CoV-2 sequences to estimate effects of mutations. We first calculate how many independent occurrences of each mutation are expected to be observed along the SARS-CoV-2 phylogeny in the absence of selection. We then compare these expected observations to the actual observations to estimate the effect of each mutation. These estimates correlate well with deep mutational scanning measurements. For most genes, synonymous mutations are nearly neutral, stop-codon mutations are deleterious, and amino-acid mutations have a range of effects. However, some viral accessory proteins are under little to no selection. We provide interactive visualizations of effects of mutations to all SARS-CoV-2 proteins (https://jbloomlab.github.io/SARS2-mut-fitness). The framework we describe is applicable to any virus for which the number of available sequences is sufficiently large that many independent occurrences of each neutral mutation are observed.

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“…The anti-SARS-COV-2 properties of Baicalein were, in part, explained through the observation of in silico interactions between this compound and 3CLpro [ 15 , 72 ]. Furthermore, a crystallographic picture of this molecular interaction was obtained with SARS-CoV-1 3CLpro [ 73 ], which has 96% similarity with SARS-CoV-2 [ 74 ].…”

Section: Discussionmentioning

confidence: 99%

Natural Flavonoid Derivatives Have Pan-Coronavirus Antiviral Activity

et al. 2023

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The SARS-CoV-2 protease (3CLpro) is one of the key targets for the development of efficacious drugs for COVID-19 treatment due to its essential role in the life cycle of the virus and exhibits high conservation among coronaviruses. Recent studies have shown that flavonoids, which are small natural molecules, have antiviral activity against coronaviruses (CoVs), including SARS-CoV-2. In this study, we identified the docking sites and binding affinity of several natural compounds, similar to flavonoids, and investigated their inhibitory activity towards 3CLpro enzymatic activity. The selected compounds were then tested in vitro for their cytotoxicity, for antiviral activity against SARS-CoV-2, and the replication of other coronaviruses in different cell lines. Our results showed that Baicalein (100 mg/mL) exerted strong 3CLpro activity inhibition (>90%), whereas Hispidulin and Morin displayed partial inhibition. Moreover, Baicalein, up to 25 mg/mL, hindered >50% of SARS-CoV-2 replication in Vero E6 cultures. Lastly, Baicalein displayed antiviral activity against alphacoronavirus (Feline-CoV) and betacoronavirus (Bovine-CoV and HCoV-OC43) in the cell lines. Our study confirmed the antiviral activity of Baicalein against SARS-CoV-2 and demonstrated clear evidence of its pan-coronaviral activity.

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Functional map of SARS-CoV-2 3CL protease reveals tolerant and immutable sites

Cited by 44 publications

References 70 publications

Structural basis of nirmatrelvir and ensitrelvir activity against naturally occurring polymorphisms of the SARS-CoV-2 main protease

Structural basis of nirmatrelvir and ensitrelvir activity against naturally occurring polymorphisms of the SARS-CoV-2 main protease

Fitness effects of mutations to SARS-CoV-2 proteins

Natural Flavonoid Derivatives Have Pan-Coronavirus Antiviral Activity

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