Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(8), С. 6495 - 6507

Опубликована: Апрель 12, 2024

We have witnessed three coronavirus (CoV) outbreaks in the past two decades, including COVID-19 pandemic caused by SARS-CoV-2. Main protease (MPro), a highly conserved among various CoVs, is essential for viral replication and pathogenesis, making it prime target antiviral drug development. Here, we leverage proteolysis targeting chimera (PROTAC) technology to develop new class of small-molecule antivirals that induce degradation SARS-CoV-2 MPro. Among them, MPD2 was demonstrated effectively reduce MPro protein levels 293T cells, relying on time-dependent, CRBN-mediated, proteasome-driven mechanism. Furthermore, exhibited remarkable efficacy diminishing SARS-CoV-2-infected A549-ACE2 cells. also displayed potent activity against strains enhanced potency nirmatrelvir-resistant viruses. Overall, this proof-of-concept study highlights potential targeted as an innovative approach developing could fight drug-resistant variants.

Язык: Английский

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SARS-CoV-2 Drug Resistance and Therapeutic Approaches

Heliyon, Год журнала: 2025, Номер 11(2), С. e41980 - e41980

Опубликована: Янв. 1, 2025

Язык: Английский

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Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04

Cell Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Апрель 9, 2024

Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, 3C-like protease (3CLpro) that confer to novel non-covalent inhibitor, WU-04, which is currently phase III clinical trials (NCT06197217). Crystallographic analysis indicates M49K mutation destabilizes WU-04-binding pocket, impacting binding WU-04 more significantly than 3CLpro substrates. The M165V directly interferes with binding. S301P mutation, far from indirectly affects by restricting rotation 3CLpro's C-terminal tail impeding dimerization. We further explored mutations clinically used inhibitors: ensitrelvir nirmatrelvir, revealed trade-off between catalytic activity, thermostability, drug 3CLpro. found at same residue (M49) can have distinct effects on inhibitors, highlighting importance developing multiple antiviral agents different skeletons for fighting These findings enhance our understanding SARS-CoV-2 mechanisms inform therapeutics.

Язык: Английский

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

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

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Generation and evaluation of protease inhibitor-resistant SARS-CoV-2 strains

Antiviral Research, Год журнала: 2024, Номер 222, С. 105814 - 105814

Опубликована: Янв. 24, 2024

Since the start of SARS-CoV-2 pandemic, search for antiviral therapies has been at forefront medical research. To date, 3CLpro inhibitor nirmatrelvir (Paxlovid®) shown best results in clinical trials and greatest robustness against variants. A second protease inhibitor, ensitrelvir (Xocova®), developed. Ensitrelvir, currently Phase 3, was approved Japan under emergency regulatory approval procedure November 2022, is available since March 31, 2023. One limitations use monotherapies emergence resistance mutations. Here, we experimentally generated mutants resistant to vitro following repeating passages presence both antivirals. For molecules, demonstrated a loss sensitivity vitro. Using Syrian golden hamster infection model, showed that M49L mutation, multi-passage strain, confers high level vivo resistance. Finally, identified recent increase prevalence M49L-carrying sequences, which appears be associated with multiple repeated events may related Xocova® country 2022. These highlight strategic importance genetic monitoring circulating strains ensure treatments administered retain their full effectiveness.

Язык: Английский

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SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs

Cell chemical biology, Год журнала: 2024, Номер 31(4), С. 632 - 657

Опубликована: Апрель 1, 2024

Over four years have passed since the beginning of COVID-19 pandemic. The scientific response has been rapid and effective, with many therapeutic monoclonal antibodies small molecules developed for clinical use. However, given ability viruses to become resistant antivirals, it is perhaps no surprise that field identified resistance nearly all these compounds. Here, we provide a comprehensive review profile each therapeutics. We hope this resource provides an atlas mutations be aware agent, particularly as springboard considerations next generation antivirals. Finally, discuss outlook thoughts moving forward in how continue manage this, next,

Язык: Английский

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

RSC Medicinal Chemistry, Год журнала: 2023, Номер 15(1), С. 81 - 118

Опубликована: Окт. 13, 2023

In order to address the world-wide health challenge caused by COVID-19 pandemic, 3CL protease/SARS-CoV-2 main protease (SARS-CoV-2-M

Язык: Английский

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The evaluation of risk factors for prolonged viral shedding during anti-SARS-CoV-2 monoclonal antibodies and long-term administration of antivirals in COVID-19 patients with B-cell lymphoma treated by anti-CD20 antibody

BMC Infectious Diseases, Год журнала: 2024, Номер 24(1)

Опубликована: Июль 22, 2024

Abstract Background The global impact of the coronavirus disease 2019 (COVID-19) pandemic has resulted in significant morbidity and mortality. Immunocompromised patients, particularly those treated for B-cell lymphoma, have shown an increased risk persistent infection with SARS-CoV-2 severe outcomes Multi-mutational variants can arise during course such cases COVID-19. No optimal, decisive strategy is currently available patients that allows clinicians to sustain viral clearance, determine optimal timing stop treatment, prevent virus reactivation. We introduced a novel treatment combining antivirals, neutralizing antibodies, genomic analysis frequent monitoring spike-specific antibody load immunocompromised COVID-19 infection. aim this retrospective study was report evaluate efficacy our lymphoma Methods This descriptive had no controls. Patients previously receiving immunotherapy including anti-CD20 diagnosed as having infection, hospital after January 2022 were included. selected anti-SARS-CoV-2 monoclonal antibodies according subvariants. Every 5 days, tested by RT-PCR, antivirals continued until shedding confirmed. Primary outcome elimination. Independent predictors prolonged time determined multivariate Cox regression. Results Forty-four included study. Thirty-five received rituximab, 19 obinutuzumab, 26 bendamustine. Median duration 10 (IQR, 10–20) days; 22 combination antiviral therapy. 16 critical 2. All survived, confirmed at median 28 19–38) days. Bendamustine use or within 1 year last multiple lines significantly shedding. Conclusions Among 44 consecutive treated, long-term administration drugs, switching, therapy elimination 100% survival. use, independent time.

Язык: Английский

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Carrimycin inhibits coronavirus replication by decreasing the efficiency of programmed –1 ribosomal frameshifting through directly binding to the RNA pseudoknot of viral frameshift-stimulatory element

Acta Pharmaceutica Sinica B, Год журнала: 2024, Номер 14(6), С. 2567 - 2580

Опубликована: Март 3, 2024

The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs broad-spectrum antiviral activity. Here, we show that carrimycin, a new macrolide antibiotic in the clinic and an candidate phase III trials, decreases efficiency programmed –1 ribosomal frameshifting coronaviruses thus impedes viral replication fashion. Carrimycin binds directly to coronaviral frameshift-stimulatory element (FSE) RNA pseudoknot, interrupting protein translation switch from ORF1a ORF1b thereby reducing level core components transcription complexes. Combined carrimycin known replicase inhibitors yielded synergistic inhibitory effect on coronaviruses. Because FSE mechanism is essential all coronaviruses, could be drug human by targeting conserved RNA. This finding may open direction discovery coronavirus variants.

Язык: Английский

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Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir

npj Viruses, Год журнала: 2024, Номер 2(1)

Опубликована: Июнь 24, 2024

Abstract The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an epidemic, zoonotically emerging pathogen initially reported in Saudi Arabia 2012. MERS-CoV has the potential to mutate or recombine with other coronaviruses, thus acquiring ability efficiently spread among humans and become pandemic. Its high mortality rate of up 35% absence effective targeted therapies call for development antiviral drugs this pathogen. Since beginning SARS-CoV-2 pandemic, extensive research focused on identifying protease inhibitors treatment SARS-CoV-2. Our intention was therefore assess whether these are viable options combating MERS-CoV. To that end, we used previously established assays quantify inhibition SARS-CoV-2, main proteases. Nirmatrelvir inhibited several proteases, whereas ensitrelvir less broadly active. simulate nirmatrelvir’s clinical use against subsequent resistance development, applied a safe, surrogate virus-based system. Using virus, selected hallmark mutations SARS-CoV-2-M pro , such as T21I, M49L, S144A, E166A/K/V L167F. In current study, pool MERS-CoV-M mutants, characterized modelled steric effect catalytic site mutants S142G, S142R, S147Y A171S.

Язык: Английский

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