Science Translational Medicine, Год журнала: 2024, Номер 16(738)
Опубликована: Март 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.
Язык: Английский
Процитировано
13Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents
Biomolecules, Год журнала: 2024, Номер 14(7), С. 797 - 797
Опубликована: Июль 4, 2024
The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus’s life cycle, making it significant target for developing antiviral drugs. inhibition Mpro has emerged as promising approach therapeutic agents to treat COVID-19. This review explores structure protein and analyzes progress made understanding protein–ligand interactions inhibitors. It focuses on binding kinetics, origin, chemical these provides in-depth analysis recent clinical trials involving covalent non-covalent inhibitors emerging dual targeting Mpro. By integrating findings from literature ongoing trials, this captures current state research into inhibitors, offering comprehensive challenges directions their future development anti-coronavirus agents. information new insights inspiration medicinal chemists, paving way more effective novel COVID-19 therapies.
Язык: Английский
Процитировано
9Transformative Approaches in SARS-CoV-2 Management: Vaccines, Therapeutics and Future Direction
Virology, Год журнала: 2025, Номер 604, С. 110394 - 110394
Опубликована: Янв. 11, 2025
Язык: Английский
Процитировано
1Progress in Research on Inhibitors Targeting SARS-CoV-2 Main Protease (Mpro)
ACS Omega, Год журнала: 2024, Номер 9(32), С. 34196 - 34219
Опубликована: Авг. 2, 2024
Since 2019, the novel coronavirus (SARS-CoV-2) has caused significant morbidity and millions of deaths worldwide. The Coronavirus Disease 2019 (COVID-19), by SARS-CoV-2 its variants, further highlighted urgent need for development effective therapeutic agents. Currently, highly conserved broad-spectrum nature main proteases (M
Язык: Английский
Процитировано
6Dual Inhibitors of SARS-CoV-2 3CL Protease and Human Cathepsin L Containing Glutamine Isosteres Are Anti-CoV-2 Agents
Journal of the American Chemical Society, Год журнала: 2025, Номер unknown
Опубликована: Янв. 2, 2025
SARS-CoV-2 3CL protease (Main protease) and human cathepsin L are proteases that play unique roles in the infection of cells by SARS-CoV-2, causative agent COVID-19. Both recognize leucine other hydrophobic amino acids at P2 position a peptidomimetic inhibitor. At P1 position, accepts many acid side chains, with partial preference for phenylalanine, while 3CL-PR has stringent specificity glutamine or analogues. We have designed, synthesized, evaluated aldehyde dual-target (dual-acting) inhibitors using two peptide scaffolds based on those Pfizer inhibitors, Nirmatrelvir, PF-835321. Our contain isosteres including 2-pyridon-3-yl-alanine, 3-pyridinyl-alanine, 1,3-oxazo-4-yl-alanine groups. Inhibition constants these new ranged from Ki = 0.6–18 nM (cathepsin L) 2.6–124 (3CL-PR), which 2-pyridon-3-yl-alanal substituent were most potent 3CL-PR. The anti-CoV-2 activity EC50 0.47–15 μM. X-ray structures similar all demonstrated formation thiohemiacetals Cys145, hydrogen-bonding interactions heteroatoms pyridon-3-yl-alanyl group, as well nitrogen N-terminal indole its appended carbonyl group P3 position. absence hydrogen bonds containing 3-pyridinyl-alanyl 1,3-oxazo-4-yl-alanyl groups was reflected less inhibition In summary, our studies demonstrate value second generation cysteine comprise single acts both protease. Such will provide anti-COVID-19 drugs remain active despite development resistance due to mutation viral more likely useful therapeutics emergence inactivating mutations because not develop resistance. This particular approach is innovative since one targets (3CL-PR) required protein maturation (hCatL) enables infection.
Язык: Английский
Процитировано
0Addition to “The Death of the Strategy of Classical Chiral Switches Is an Exaggeration”
ACS Medicinal Chemistry Letters, Год журнала: 2025, Номер 16(2), С. 344 - 346
Опубликована: Янв. 6, 2025
[This corrects the article DOI: 10.1021/acsmedchemlett.4c00450.].
Язык: Английский
Процитировано
0Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease
Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown
Опубликована: Янв. 16, 2025
The main protease Mpro is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among first reported inhibitors was peptidomimetic α-ketoamide 13b, whose cocrystal structure with paved way for multiple lead-finding studies. We established structure-activity relationships 13b series modifying residues at P1', P3, and P4 sites. Guided structures, we reduced P1' substituent size better fill pocket added fluorine pyridone ring, enabling new hydrogen bond Gln189 in P3. 22 novel analogues, 6d 12d inhibited IC50s of 110 nM 40 nM, improving potency up 9.5-fold. Compound had pronounced antiviral activity an EC50 1.6 μM stable plasma microsomes. study illustrates potential structure-based design systematically improve α-ketoamides.
Язык: Английский
Процитировано
0Investigating the inhibition of benzimidazole derivatives on SARS-CoV-2 M pro by enzyme activity inhibition, spectroscopy, and molecular docking
Journal of Biomolecular Structure and Dynamics, Год журнала: 2025, Номер unknown, С. 1 - 16
Опубликована: Фев. 19, 2025
The inhibition of twenty-five 1,2-fused/disubstituted benzimidazoles on the SARS-CoV-2 Mpro were investigated in this work. It was found that four compounds (1i, 1k, 1l, and 1m) showed obvious inhibitory effect Mpro. 1k (IC50 46.86 μM) best. UV-vis, fluorescence, CD molecular docking methods used to reveal mechanisms interaction between these Results indicated static quenching main type quenching. 1i, 1m may alter conformation microenvironment dominant forces 1i (or 1l) hydrogen bonds or van der Waals forces. electrostatic hydrophobic forces, which consistent with results docking. influence structure binding investigated. Chlorine atom groups favorable for derivative inhibitors This work confirmed changes micro-environment by provided clues design potential inhibitors.
Язык: Английский
Процитировано
0Research progress and perspectives of dual-target inhibitors
European Journal of Medicinal Chemistry, Год журнала: 2025, Номер 289, С. 117453 - 117453
Опубликована: Фев. 26, 2025
Язык: Английский
Процитировано
0Development of antiviral drugs for COVID-19 in 2025: unmet needs and future challenges
Expert Review of Anti-infective Therapy, Год журнала: 2025, Номер unknown
Опубликована: Фев. 25, 2025
The success in the COVID-19 pandemic containment largely originated from vaccine- and infection-elicited immunity, with SARS-CoV-2 infection only marginally mitigated by availability of antiviral drugs. current lack effective prophylactic therapeutic agents immunocompromised patients highlights need for a radical change design both drug manufacturing clinical trials. In this review authors summarize their suggestions manufacturers, reviewing classes small molecule antivirals passive immunotherapies highlighting limitations unexploited potential. Molecular serological testing can improve appropriateness. Efficacy be improved combining different while preserving economical sustainability. Respiratory delivery should better investigated
Язык: Английский
Процитировано
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