An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(738)

Published: March 13, 2024

Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M pro ) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing severity COVID-19, but presence resistance-conferring mutations sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized covalent hepatitis C virus inhibitor boceprevir (BPV) could serve basis for orally bioavailable inhibit SARS-CoV-2 M more efficiently than existing drugs. Performing structure-guided modifications BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, pharmacokinetics, therapeutic efficacy similar or superior to those NTV. A crucial feature ML2006a4 is derivatization ketoamide reactive group improves cell permeability bioavailability. Last, was found be less sensitive several cause resistance NTV ETV occur natural population. Thus, anticipatory design can preemptively address potential mechanisms expand treatment options variants.

Language: Английский

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

Chemical Science, Journal Year: 2024, Volume and Issue: 15(20), P. 7667 - 7678

Published: Jan. 1, 2024

Thiophene-fused γ-lactams are reversible covalent inhibitors of the SARS-CoV-2 main protease, a nucleophilic cysteine enzyme. γ-Lactams can inhibit enzymes by S -acylation as well serine O -acylation.

Language: Английский

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Research Progress on the Structure and Function, Immune Escape Mechanism, Antiviral Drug Development Methods, and Clinical Use of SARS-CoV-2 Mpro

Molecules, Journal Year: 2025, Volume and Issue: 30(2), P. 351 - 351

Published: Jan. 16, 2025

The three-year COVID-19 pandemic ‘has’ caused a wide range of medical, social, political, and financial implications. Since the end 2020, various mutations variations in SARS-CoV-2 strains, along with immune escape phenomenon, have emerged. There is an urgent need to identify relatively stable target for development universal vaccines drugs that can effectively combat both strains their mutants. Currently, main focus treating lies disrupting virus’s life cycle. protease (Mpro) closely associated virus replication maturation plays crucial role early stages infection. Consequently, it has become important SARS-CoV-2-specific drugs. This review summarizes recent research progress on novel coronavirus’s proteases, including pivotal Mpro cycle, structure catalytic mechanism Mpro, self-maturation escape, current methods developing antiviral targeting key successfully entered clinical trials. aim provide researchers involved systematic comprehensive information.

Language: Английский

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Identification of lead small molecules for the design and development of potent severe acute respiratory syndrome coronavirus 2 main protease inhibitors

Journal of Chemical Research, Journal Year: 2025, Volume and Issue: 49(2)

Published: March 1, 2025

The repercussions of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are catastrophic, and world has yet to achieve full recovery. Several inhibitors targeting SARS-CoV-2 main protease experiencing diminished efficacy owing resistance-inducing mutations. current situation implies that quest find potent resilient drugs overcome resistance must be a continuous effort. Here, multiple receptor virtual screening molecular dynamics (MD) simulation techniques were employed identify novel binders from an integrated small-molecule database as leads for discovery, design, development antivirals immune protease. was initially screened separately against five structures with different substrate-binding site conformations using GOLD program, after which fitness score control compound used cutoff create shortlist potential hits in each case. Then, 21 compounds at intersection all shortlists selected hits. subjected MD simulations, identifying four capable remaining bound up 100 ns. Analysis mode binding interactions between revealed fit better into conserved subpockets than interact important amino acid residues. Conjointly, energy, toxicity analysis results further demonstrated promising augment fight resistance.

Language: Английский

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Silaproline-bearing nirmatrelvir derivatives are potent inhibitors of the SARS-CoV-2 main protease highlighting the value of silicon-derivatives in structure-activity-relationship studies

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117603 - 117603

Published: April 1, 2025

Nirmatrelvir is a substrate-related inhibitor of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) main protease (Mpro) that clinically used in combination with ritonavir to treat COVID-19. Derivatives nirmatrelvir, modified at substrate P2-equivalent position, have been developed fine-tune properties and are now clinical use. We report synthesis nirmatrelvir derivatives (R)-4,4-dimethyl-4-silaproline (silaproline) group position. Mass spectrometry (MS)-based assays demonstrate silaproline-bearing efficiently inhibit isolated recombinant Mpro, albeit reduced potency compared nirmatrelvir. Investigations SARS-CoV-2 infected VeroE6 cells reveal inhibitors CF3 P4-equivalent position viral progression, implying incorporating silicon atoms into Mpro can yield vivo active appropriate optimization. MS crystallographic studies show nucleophilic site cysteine residue (Cys145) reacts nitrile inhibitors. Substituting electrophilic for non-activated terminal alkyne shifts inhibition mode from reversible covalent irreversible inhibition. One two prochiral silaproline methyl groups occupies space S2 pocket unoccupied Mpro:nirmatrelvir complex structures, highlighting value sila-derivatives structure-activity-relationship (SAR) studies. The combined results highlight potential silicon-containing molecules and, by implication, other enzymes.

Language: Английский

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Development of Orally Bioavailable Octahydroindole-Based Peptidomimetic Derivative as a Broad-Spectrum Inhibitor against HCoV-OC43 and SARS-CoV-2

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: May 22, 2025

A series of novel Mpro inhibitors was designed and synthesized to combat the coronavirus, such as HCoV-OC43 SARS-CoV-2, several compounds showed comparable antiviral activity nirmatrelvir. Among them, an octahydroindole-based peptidomimetic covalent inhibitor 28f strong inhibitory against Mpros exhibited broad-spectrum anticoronavirus with EC50 values ranging from 0.027 4.41 μM. Besides, this compound displayed potent EV71. Compared FB2001, better pharmacokinetic properties, value oral bioavailability in CD-1 mice Beagle dogs improved 10.4 10.2%, respectively. In addition, treatment could significantly reduce viral loads mice, also effectively lung a K18-hACE2 transgenic mouse model without ritonavir. Taken together, is promising orally bioavailable drug candidate that deserves further research.

Language: Английский

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Influence of Steric and Electronic Properties of P2 Groups on Covalent Inhibitor Binding to SARS-CoV-2 Main Protease

ACS Infectious Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: May 29, 2025

The main protease (MPro) of SARS-CoV-2 is a critical enzyme required for viral replication, making it prime target antiviral drug development. Covalent inhibitors, which form stable interaction with the catalytic C145, have demonstrated strong inhibition MPro, but influence steric and electronic properties P2 substituents, designed to engage S2 substrate-binding subsite within MPro active site, on inhibitor binding affinity remains underexplored. In this study, we design characterize two hybrid covalent BBH-3 BBH-4, present their X-ray crystallographic structures in complex providing molecular insights into how distinct groups, dichlorobenzyl moiety an adamantyl substituent affect conformation site adaptability. Comparative structural analyses previously characterized including BBH-2 Mcule-5948770040, reveal bulkiness dynamics, particularly through interactions S5 subsites. group induces conformational shifts helix loop, while BBH-4 displaces M49, stabilizing its hydrophobic interactions. Isothermal titration calorimetry further elucidates impact modifications affinity, revealing delicate balance between enthalpic entropic contributions. data demonstrate that exhibits less favorable binding, affirming substitution at position has more negative than bulky saturated cyclic groups. This underscores feature malleability may be accompanied by strain.

Language: Английский

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

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(14), P. 11656 - 11661

Published: July 5, 2024

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

Language: Английский

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Crystal structures of coronaviral main proteases in complex with the non-covalent inhibitor X77

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 276, P. 133706 - 133706

Published: July 7, 2024

Language: Английский

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Effects of SARS-CoV-2 Main Protease Mutations at Positions L50, E166, and L167 Rendering Resistance to Covalent and Noncovalent Inhibitors

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(20), P. 18478 - 18490

Published: Oct. 7, 2024

SARS-CoV-2 propagation under nirmatrelvir and ensitrelvir pressure selects for main protease (MPro) drug-resistant mutations E166V (DRM2), L50F/E166V (DRM3), E166A/L167F (DRM4), L50F/E166A/L167F (DRM5). DRM2-DRM5 undergoes N-terminal autoprocessing to produce mature MPro with dimer dissociation constants (Kdimer) 2–3 times larger than that of the wildtype. Co-selection L50F restores catalytic activity DRM2 DRM4 from ∼10 30%, relative wild-type enzyme, without altering Kdimer. Binding affinities thermodynamic profiles parallel drug selection pressure, exhibiting significant decreases in affinity through entropy/enthalpy compensation, were compared GC373. Reorganization active sites due observed inhibitor-free DRM3 structures as MProWT may account reduced binding affinities, although complexes are almost identical MProWT-ensitrelvir. Chemical reactivity changes mutant differences electrostatic protein dynamics effects likely contribute losses affinities.

Language: Английский

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