Pharmacological disruption of mSWI/SNF complex activity restricts SARS-CoV-2 infection

Nature Genetics, Год журнала: 2023, Номер 55(3), С. 471 - 483

Опубликована: Март 1, 2023

Abstract Identification of host determinants coronavirus infection informs mechanisms viral pathogenesis and can provide new drug targets. Here we demonstrate that mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) chromatin remodeling complexes, specifically canonical BRG1/BRM-associated factor (cBAF) promote severe acute respiratory syndrome 2 (SARS-CoV-2) represent host-directed therapeutic The catalytic activity SMARCA4 is required for mSWI/SNF-driven accessibility at the ACE2 locus, expression virus susceptibility. transcription factors HNF1A/B interact with recruit mSWI/SNF complexes to enhancers, which contain high HNF1A motif density. Notably, small-molecule ATPase inhibitors or degraders abrogate angiotensin-converting enzyme (ACE2) confer resistance SARS-CoV-2 variants a remdesivir-resistant in three cell lines primary human types, including airway epithelial cells, by up 5 logs. These data highlight role complex activities conferring susceptibility identify potential class broad-acting antivirals combat emerging coronaviruses drug-resistant variants.

Язык: Английский

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Rapid resistance profiling of SARS-CoV-2 protease inhibitors

npj Antimicrobials and Resistance, Год журнала: 2023, Номер 1(1)

Опубликована: Авг. 20, 2023

Abstract Resistance to nirmatrelvir (Paxlovid) has been shown by multiple groups and may already exist in clinical SARS-CoV-2 isolates. Here a robust cell-based assay is used determine the relative potencies of nirmatrelvir, ensitrelvir, FB2001 against panel main protease (M pro ) variants. The results reveal that these three drugs have at least partly distinct resistance mutation profiles raise possibility latter compounds be effective some instances Paxlovid vice versa .

Язык: Английский

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Preparing for the next viral threat with broad-spectrum antivirals

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(11)

Опубликована: Май 31, 2023

There is a large global unmet need for the development of countermeasures to combat hundreds viruses known cause human disease and establishment therapeutic portfolio future pandemic preparedness. Most approved antiviral therapeutics target proteins encoded by single virus, providing narrow spectrum coverage. This, combined with slow pace high cost drug development, limits scalability this direct-acting (DAA) approach. Here, we summarize progress challenges in broad-spectrum antivirals that either viral elements (proteins, genome structures, lipid envelopes) or cellular proviral factors co-opted multiple via newly discovered compounds repurposing drugs. These strategies offer new means developing against both existing emerging threats complement DAAs.

Язык: Английский

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In vitro and in vivo characterization of SARS-CoV-2 strains resistant to nirmatrelvir

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 4, 2023

Nirmatrelvir, an oral antiviral agent that targets a SARS-CoV-2 main protease (3CLpro), is clinically useful against infection with including its omicron variants. Since most subvariants have reduced sensitivity to many monoclonal antibody therapies, potential resistance nirmatrelvir major public health concern. Several amino acid substitutions been identified as being responsible for susceptibility nirmatrelvir. Among them, we selected L50F/E166V and L50F/E166A/L167F in the 3CLpro because these combinations of are unlikely affect virus fitness. We prepared characterized delta variants possessing Nsp5-L50F/E166V Nsp5-L50F/E166A/L167F. Both mutant viruses showed decreased their growth VeroE6/TMPRSS2 cells was delayed. attenuated phenotypes male hamster model, maintained airborne transmissibility, were outcompeted by wild-type co-infection experiments absence nirmatrelvir, but less so presence drug. These results suggest Nsp5-L50F/E166A/L167F do not become dominant nature. However, it important closely monitor emergence nirmatrelvir-resistant resistant additional compensatory mutations could emerge, outcompete virus, dominant.

Язык: Английский

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Multiplexed discrimination of SARS-CoV-2 variants via plasmonic-enhanced fluorescence in a portable and automated device

Nature Biomedical Engineering, Год журнала: 2023, Номер 7(12), С. 1636 - 1648

Опубликована: Сен. 21, 2023

Язык: Английский

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SARS-CoV-2 Mpro Inhibitors: Achieved Diversity, Developing Resistance and Future Strategies

Future Pharmacology, Год журнала: 2023, Номер 3(1), С. 80 - 107

Опубликована: Янв. 9, 2023

While the COVID-19 pandemic seems to be on its decline, unclear impacts of long-COVID cases, breakthrough infections in immunocompromised individuals, vaccine hesitancy, and inhomogeneous health-care accessibility constitute a not underestimated threat. These along with preparedness, ask for an alert identification new drugs optimization existing as therapeutic treatment options this potential future diseases. Mpro inhibitors were identified early potent drug candidates against coronaviruses, since they target viable processing machinery within virus, i.e., main protease that cleaves polyproteins encoded by viral RNA into functional proteins. Different strategies, including reversible irreversible inhibition well allosteric inhibitors, mostly from repurposing endeavors, have been explored design SARS-CoV-2 antivirals. Ambitious screening efforts uttered outstanding chemical structural diversity, which has led half dozen lead compounds being currently clinical trials emergency FDA approval ritonavir-boosted nirmatrelvir therapeutic. This comprehensive analysis achieved inhibitor diversity sorted irreversible, reversible, binders, discussion emerging resistance reports possible evasion is aimed at stimulating continuing efforts.

Язык: Английский

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Systematic Analyses of the Resistance Potential of Drugs Targeting SARS-CoV-2 Main Protease

ACS Infectious Diseases, Год журнала: 2023, Номер 9(7), С. 1372 - 1386

Опубликована: Июнь 30, 2023

Drugs that target the main protease (Mpro) of SARS-CoV-2 are effective therapeutics have entered clinical use. Wide-scale use these drugs will apply selection pressure for evolution resistance mutations. To understand potential in Mpro, we performed comprehensive surveys amino acid changes can cause to nirmatrelvir (Pfizer), and ensitrelvir (Xocova) a yeast screen. We identified 142 mutations 177 ensitrelvir, many which not been previously reported. Ninety-nine caused apparent both inhibitors, suggesting likelihood cross-resistance. The mutation with strongest drug score against our study (E166V) was most impactful recently reported multiple viral passaging studies. Many exhibited inhibitor-specific were consistent distinct interactions each inhibitor substrate binding site. In addition, mutants strong scores tended reduced function. Our results indicate from or select distinct-resistant lineages include primary weaken while decreasing enzyme function compensatory increase activity. identification enables design inhibitors developing aids surveillance circulating populations.

Язык: Английский

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The impact of SARS-CoV-2 3CL protease mutations on nirmatrelvir inhibitory efficiency. Computational insights into potential resistance mechanisms

Chemical Science, Год журнала: 2023, Номер 14(10), С. 2686 - 2697

Опубликована: Янв. 1, 2023

The use of antiviral drugs can promote the appearance mutations in target protein that increase resistance virus to treatment. This is also case nirmatrelvir, a covalent inhibitor 3CL protease, or main SARS-CoV-2. In this work we show how by-residue decomposition noncovalent interactions established between drug and enzyme, combination with an analysis naturally occurring mutations, be used detect potential protease conferring nirmatrelvir. We investigate consequences these on reaction mechanism form enzyme-inhibitor complex using QM/MM methods. particular, E166V variant displays smaller binding affinity nirmatrelvir larger activation free energy for formation complex, both factors contributing observed treatment drug. conclusions derived from our anticipate introduction fitness landscape design new inhibitors adapted some possible mechanisms.

Язык: Английский

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Structural biology of SARS-CoV-2 Mpro and drug discovery

Current Opinion in Structural Biology, Год журнала: 2023, Номер 82, С. 102667 - 102667

Опубликована: Авг. 4, 2023

Язык: Английский

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Comparing molnupiravir and nirmatrelvir/ritonavir efficacy and the effects on SARS-CoV-2 transmission in animal models

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Авг. 7, 2023

Abstract Therapeutic options against SARS-CoV-2 are underutilized. Two oral drugs, molnupiravir and paxlovid (nirmatrelvir/ritonavir), have received emergency use authorization. Initial trials suggested greater efficacy of paxlovid, but recent studies indicated comparable potency in older adults. Here, we compare both drugs two animal models; the Roborovski dwarf hamster model for severe COVID-19-like lung infection ferret transmission model. Dwarf hamsters treated with either drug survive VOC omicron equivalent titer reduction. Viral RNA copies upper respiratory tract female ferrets receiving 1.25 mg/kg twice-daily not significantly reduced, infectious titers lowered by >2 log orders direct-contact is stopped. Female dosed 20 or 100 nirmatrelvir/ritonavir show 1–2 order reduction viral titers, which correlates low nirmatrelvir exposure nasal turbinates. Virus replication resurges towards treatment end virus transmits efficiently (20 group) partially (100 group). Prophylactic does prevent spread from infected ferrets, prophylactic 5 block productive transmission. These data confirm reports similar adults inform on possible epidemiologic benefit antiviral treatment.

Язык: Английский

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