On the origins of SARS-CoV-2 main protease inhibitors

Janin, Yves L.

doi:10.1039/d3md00493g

Cited by 12 publications

(3 citation statements)

References 370 publications

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“…1), an enzyme in SARS-CoV-2, plays a vital role in viral replication via proteolytic processing. M pro is regarded as one of the principal targets for developing oral antiviral drugs against COVID-19 [10][11][12][13][14][15][16][17]. M pro exhibits catalytic activity in the hydrolysis reaction that cleaves polyproteins generated via translation after SARS-CoV-2 infection.…”

Section: Introductionmentioning

confidence: 99%

Exploring multiple reaction pathways in the proteolysis of SARS-CoV-2 main protease through large-scale quantum molecular dynamics

Ono,

Koshimizu,

Fukunishi

et al. 2024

Preprint

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Elucidation of the enzymatic reaction mechanism of the main protease (Mpro) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is significant for the development of peptidomimetic covalent inhibitors against coronavirus disease 2019 (COVID-19) such as nirmatrelvir. Large-scale quantum molecular dynamics and metadynamics simulations were performed for wild-type Mpro dimer, monomer, and nirmatrelvir-resistant mutant with natural substrate models. The study primarily focused on the acylation stage of the catalytic cycle, which involves covalent bond formation between the enzyme and the ligand. Free energy analyses revealed that nucleophilic acyl substitution, characterized by intra-protein proton transfer, nucleophilic substitution, and proton transfer between the protein and substrate, occurs via two pathways with comparable free energy barriers in the wild-type Mpro dimer. The study revealed that the free energy barriers for the two reaction pathways in the monomer were marginally higher than those in the dimer, suggesting that dimerization contributes to the stabilization of the active-site structure, which is crucial for facilitating chemical reactions. Additionally, the nirmatrelvir-resistant mutant was observed to destabilize the intermediate state during the nucleophilic substitution process. This finding illustrates that despite the mutation conferring drug resistance, the enzymatic reactivity is preserved by altering the reaction mechanism, thereby maintaining the protease’s functionality.

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Section: Introductionmentioning

confidence: 99%

Exploring multiple reaction pathways in the proteolysis of SARS-CoV-2 main protease through large-scale quantum molecular dynamics

Ono,

Koshimizu,

Fukunishi

et al. 2024

Preprint

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“…14,15,42 Many investigational M pro inhibitors, however, employ highly reactive electrophiles for covalent reaction with Cys145, including e.g. , aldehydes, α-ketoamides, and Michael acceptors, 19,43,44 which may potentially compromise safety, as reported for some clinically-used small-molecules bearing reactive electrophiles; 26,45 The use of electrophilic groups with relatively low intrinsic reactivity is thus desirable. The observation that the γ-lactam of both 1 and 2 is stable in cells 14,15 likely reflects its reduced reactivity compared to more reactive electrophiles, indicating that covalently reacting γ-lactams may have potential for development of safe COVID-19 therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Thiophene-fused γ-lactams inhibit the SARS-CoV-2 main protease via reversible covalent acylation

Gayatri,

Brewitz,

Ibbotson

et al. 2024

Chem. Sci.

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“…Nirmatrelvir (PF-07321332; 1 ) is a first-in-class small-molecule inhibitor of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) main protease (M pro /3C-like protease), which is used clinically in combination with ritonavir under the brand-name paxlovid to treat and/or hinder SARS-CoV-2 infections (Figure a). , M pro is a nucleophilic cysteine protease that catalyzes the hydrolysis of viral polyproteins pp1a/1ab to give functional nonstructural proteins; − M pro inhibition disrupts the viral life cycle and halts viral replication. − Work leading to the development of paxlovid, which was carried out under intense time and social pressure during the COVID-19 pandemic, was a major breakthrough, because it validated inhibition of M pro as a treatment for COVID-19. , Paxlovid treatment complements vaccination campaigns and provides a safe means to cure infections in vulnerable groups; , along with several other clinically approved M pro inhibitors subsequently reported by others, − it has contributed to reducing the death rate associated with SARS-CoV-2 infections and helped enable a return to pre-COVID-19 lifestyles.…”

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confidence: 99%

Fixing the Achilles Heel of Pfizer’s Paxlovid for COVID-19 Treatment

Brewitz,

Schofield

2024

J. Med. Chem.

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Nirmatrelvir (PF-07321332), a first-in-class inhibitor of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) main protease (M pro ), was developed by Pfizer under intense pressure during the pandemic to treat COVID-19. A weakness of nirmatrelvir is its limited metabolic stability, which led to the development of a combination therapy (paxlovid), involving coadministration of nirmatrelvir with the cytochrome P450 inhibitor ritonavir. However, limitations in tolerability of the ritonavir component reduce the scope of paxlovid. In response to these limitations, researchers at Pfizer have now developed the secondgeneration M pro inhibitor PF-07817883 (ibuzatrelvir). Structurally related to nirmatrelvir, including with the presence of a trifluoromethyl group, albeit located differently, ibuzatrelvir manifests enhanced oral bioavailability, so it does not require coadministration with ritonavir. The development of ibuzatrelvir is an important milestone, because it is expected to enhance the treatment of COVID-19 without the drawbacks associated with ritonavir. Given the success of paxlovid in treating COVID-19, it is likely that ibuzatrelvir will be granted approval as an improved drug for treatment of COVID-19 infections, so complementing vaccination efforts and improving pandemic preparedness. The development of nirmatrelvir and ibuzatrelvir dramatically highlights the power of appropriately resourced modern medicinal chemistry to very rapidly enable the development of breakthrough medicines. Consideration of how analogous approaches can be used to develop similarly breakthrough medicines for infectious diseases such as tuberculosis and malaria is worthwhile.

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On the origins of SARS-CoV-2 main protease inhibitors

Abstract: In order to address the world-wide health challenge caused by the COVID-19 pandemic, the 3CL protease/SARS-CoV-2 main protease (SARS-CoV-2-Mpro) coded by its nsp5 gene became one of the biochemical targets...

Cited by 12 publications

References 370 publications

Exploring multiple reaction pathways in the proteolysis of SARS-CoV-2 main protease through large-scale quantum molecular dynamics

Exploring multiple reaction pathways in the proteolysis of SARS-CoV-2 main protease through large-scale quantum molecular dynamics

Thiophene-fused γ-lactams inhibit the SARS-CoV-2 main protease via reversible covalent acylation

Fixing the Achilles Heel of Pfizer’s Paxlovid for COVID-19 Treatment

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