The Path to Paxlovid

Halford, Bethany

doi:10.1021/acscentsci.2c00369

Cited by 50 publications

(55 citation statements)

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“…In addition, two orally available small molecules have recently been introduced as anti-SARS-CoV-2 drugs. Molnupiravir (Lagevrio ® ) increases the frequency of viral RNA mutations, impairing SARS-CoV-2 replication [ 7 , 8 ], while Nirmatrelvir (Paxlovid ® ) acts by inhibiting the SARS-CoV-2 main protease [ 9 , 10 ]. These two drugs are now available for the treatment of SARS-CoV-2-infected individuals who do not require supplemental oxygen, and who are at increased risk of developing severe COVID-19.…”

Section: Introductionmentioning

confidence: 99%

Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein

Weißenborn

Richel

Hüseman

et al. 2022

IJMS

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Based on the structure of a de novo designed miniprotein (LCB1) in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, we have generated and characterized truncated peptide variants of LCB1, which present only two of the three LCB1 helices, and which fully retained the virus neutralizing potency against different SARS-CoV-2 variants of concern (VOC). This antiviral activity was even 10-fold stronger for a cyclic variant of the two-helix peptides, as compared to the full-length peptide. Furthermore, the proteolytic stability of the cyclic peptide was substantially improved, rendering it a better potential candidate for SARS-CoV-2 therapy. In a more mechanistic approach, the peptides also served as tools to dissect the role of individual mutations in the RBD for the susceptibility of the resulting virus variants to neutralization by the peptides. As the peptides reported here were generated through chemical synthesis, rather than recombinant protein expression, they are amenable to further chemical modification, including the incorporation of a wide range of non-proteinogenic amino acids, with the aim to further stabilize the peptides against proteolytic degradation, as well as to improve the strength, as well the breadth, of their virus neutralizing capacity.

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Section: Introductionmentioning

confidence: 99%

Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein

Weißenborn

Richel

Hüseman

et al. 2022

IJMS

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“…Its less peptidomimetic structure (fewer H-bond donors and lower polarity compared to the parent compound) and the insertion of a trifluoroacetamide moiety guaranteed excellent intestinal barrier permeation and excellent oral bioavailability compared to the first in vivo evaluations. 21 , 86 …”

Section: Electrophilic Warheads In Covalent Sars-cov-2 M Pr...mentioning

confidence: 99%

“…PF-07321332, a nitrile compound developed by Pfizer as a covalent SARS-CoV-2 M PRO inhibitor, entered clinical trials in combination with ritonavir showing promising results in phase 2/3 (PAXLOVID) and was recently approved by the Committee for Medicinal Products for Human use of the EMA for the treatment of COVID-19. 21 − 23…”

Section: Introductionmentioning

confidence: 99%

“…In the last 2 years, the whole scientific community has invested a lot of time and resources to design new covalent SARS-CoV-2 M PRO inhibitors, and in this context, some small molecules have already reached the most advanced phases of drug development. PF-07321332, a nitrile compound developed by Pfizer as a covalent SARS-CoV-2 M PRO inhibitor, entered clinical trials in combination with ritonavir showing promising results in phase 2/3 (PAXLOVID) and was recently approved by the Committee for Medicinal Products for Human use of the EMA for the treatment of COVID-19. − …”

Section: Introductionmentioning

confidence: 99%

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Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure–Activity Relationship Insights and Evolution Perspectives

et al. 2022

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The viral main protease is one of the most attractive targets among all key enzymes involved in the SARS-CoV-2 life cycle. Covalent inhibition of the cysteine 145 of SARS-CoV-2 M PRO with selective antiviral drugs will arrest the replication process of the virus without affecting human catalytic pathways. In this Perspective, we analyzed the in silico, in vitro, and in vivo data of the most representative examples of covalent SARS-CoV-2 M PRO inhibitors reported in the literature to date. In particular, the studied molecules were classified into eight different categories according to their reactive electrophilic warheads, highlighting the differences between their reversible/irreversible mechanism of inhibition. Furthermore, the analyses of the most recurrent pharmacophoric moieties and stereochemistry of chiral carbons were reported. The analyses of noncovalent and covalent in silico protocols, provided in this Perspective, would be useful for the scientific community to discover new and more efficient covalent SARS-CoV-2 M PRO inhibitors.

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“…The SARS-CoV-2 M pro also cleaves important signaling proteins of the host cell such as NEMO, the essential modulator of nuclear factor-κB, thereby causing some of the neurologic symptoms of COVID-19 and blocking type-I interferon production . Because of its important role in viral polyprotein and host protein processing, inhibition of M pro has proven to be a viable strategy for the development of a coronavirus therapeutic …”

Section: Introductionmentioning

confidence: 99%

Diastereomeric Resolution Yields Highly Potent Inhibitor of SARS-CoV-2 Main Protease

Cooper¹,

Zhang

Ibrahim

et al. 2022

J. Med. Chem.

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SARS-CoV-2 is the causative agent behind the COVID-19 pandemic. The main protease (Mpro, 3CLpro) of SARS-CoV-2 is a key enzyme that processes polyproteins translated from the viral RNA. Mpro is therefore an attractive target for the design of inhibitors that block viral replication. We report the diastereomeric resolution of the previously designed SARS-CoV-2 Mpro α-ketoamide inhibitor 13b. The pure (S,S,S)-diastereomer, 13b-K, displays an IC50 of 120 nM against the Mpro and EC50 values of 0.8–3.4 μM for antiviral activity in different cell types. Crystal structures have been elucidated for the Mpro complexes with each of the major diastereomers, the active (S,S,S)-13b (13b-K), and the nearly inactive (R,S,S)-13b (13b-H); results for the latter reveal a novel binding mode. Pharmacokinetic studies show good levels of 13b-K after inhalative as well as after peroral administration. The active inhibitor (13b-K) is a promising candidate for further development as an antiviral treatment for COVID-19.

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The Path to Paxlovid

Cited by 50 publications

References 0 publications

Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein

Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein

Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure–Activity Relationship Insights and Evolution Perspectives

Diastereomeric Resolution Yields Highly Potent Inhibitor of SARS-CoV-2 Main Protease

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